Crystalline 19-nor C3,3-disubstituted C21-N-pyrazolyl steroid

ABSTRACT

This invention relates to a 19-nor C3,3-disubstituted C21-pyrazolyl steroid of Formula (I) and crystalline solid forms and compositions thereof. Also disclosed herein are methods of making crystalline solid forms of the 19-nor C3,3-disubstituted C21-pyrazolyl steroid of Formula (I) and methods of using the 19-nor C3,3-disubstituted C21-pyrazolyl steroid of Formula (I) or crystalline solid forms, pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase Application under 35U.S.C. § 371 of International Application PCT/US2017/048267, filed Aug.23, 2017, which claims priority to U.S. Ser. No. 62/378,582 filed Aug.23, 2016, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of approximately −70 mV, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K⁺,Na⁺, Cl⁻, organic anions) balance across the neuronal semipermeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased under the influence of neuronal action potentials. Whenreleased into the synaptic cleft, an excitatory chemical transmittersuch as acetylcholine will cause membrane depolarization (change ofpotential from −70 mV to −50 mV). This effect is mediated bypostsynaptic nicotinic receptors which are stimulated by acetylcholineto increase membrane permeability to Na ions. The reduced membranepotential stimulates neuronal excitability in the form of a postsynapticaction potential.

In the case of the γ-aminobutyric acid receptor complex (GRC), theeffect on brain excitability is mediated by γ-aminobutyric acid (GABA),a neurotransmitter. GABA has a profound influence on overall brainexcitability because up to 40% of the neurons in the brain utilize GABAas a neurotransmitter. GABA regulates the excitability of individualneurons by regulating the conductance of chloride ions across theneuronal membrane. GABA interacts with its recognition site on the GRCto facilitate the flow of chloride ions down an electrochemical gradientof the GRC into the cell. An intracellular increase in the levels ofthis anion causes hyperpolarization of the transmembrane potential,rendering the neuron less susceptible to excitatory inputs (i.e.,reduced neuron excitability). In other words, the higher the chlorideion concentration in the neuron, the lower the brain excitability (thelevel of arousal).

New and improved neuroactive crystalline forms of steroids are neededthat act as modulating agents for brain excitability, as well as agentsfor the prevention and treatment of CNS-related diseases. Crystallineforms of such a steroid described herein are directed toward this end.

SUMMARY OF THE INVENTION

The present invention relates, in part, to novel forms (for example,certain crystalline forms described herein) of a 19-nor (i.e., C19desmethyl) compound. Generally, a solid compound's efficacy as a drugcan be affected by the properties of the solid it comprises.

Thus, in one aspect, described herein is a crystalline compound ofFormula (I):

also referred to herein as “Compound 1.”

In some embodiments, a solubilized form of the crystalline form ofCompound 1 is converted to a different crystalline form of Compound 1 byslow evaporation, anti-solvent addition, slow-cooling, solution vapordiffusion, solid vapor diffusion, fast evaporation, reverse anti-solventaddition, and water activity experiments.

In some embodiments, a crystalline form of Compound 1 is converted to adifferent crystalline form of Compound 1 by slurry conversion.

In some embodiments, physical or chemical parameters of a solid form ofCompound 1 are evaluated from one or more of the following analyticaltechniques: X-ray powder diffraction (XRPD) analysis, e.g.,variable-temperature XRPD (VT-XRPD) analysis, single-crystal X-raycrystallography, thermogravimetric analysis (TGA), differential scanningcalorimetry (DSC), nuclear magnetic resonance (NMR) spectroscopy orsolid-state NMR spectroscopy, Raman spectroscopy, or dynamic vaporsorption (DVS).

In embodiments, each solid form is characterized and identified withparameters obtained from one or more of the aforementioned analyticalmethods:

X-ray diffraction patterns presented with degrees 2-theta (2θ) as theabscissa and peak intensity as the ordinate as determined by analysiswith XRPD. These patterns are also referred to herein as XRPD patterns;

properties of the single-crystal structure of a solid form, e.g., unitcell, crystal system, and space group, as determined by single-crystalX-ray crystallography;

calculated XRPD patterns for a crystalline form as determined by datafrom single-crystal X-ray crystallography;

an endotherm specified by an onset temperature Toner that indicates aloss of solvent, a transformation from one crystalline form to another,or a melting point as determined by DSC performed at a specific ramprate;

a value for weight loss as determined by TGA;

a value for weight gain at a temperature of 25° C. and a relativehumidity between 5% and 95% as determined by DVS; and

an exemplary ¹H NMR spectrum of Compound 1 dissolved in deuterateddimethyl sulfoxide (DMSO-d₆).

In embodiments, a solid form is determined to be crystalline by thepresence of sharp, distinct peaks found in the corresponding XRPDpattern.

In some embodiments, XRPD is used to determine if a solid form ofCompound 1 transforms to another solid form at temperatures higher thanroom temperature.

In some embodiments, crystalline Compound 1 is an anhydrate.

In some embodiments, crystalline Compound 1 is a solvate.

In some embodiments, crystalline Compound 1 can have an XRPD patternwith characteristic peaks between and including the following values of2θ in degrees: 11.6 to 12.0 (e.g., 11.8), 13.7 to 14.1 (e.g., 13.9),14.0 to 14.4 (e.g., 14.2), 16.6 to 17.0 (e.g., 16.8), 18.9 to 19.3(e.g., 19.1), 19.1 to 19.5 (e.g., 19.3), 19.9 to 20.3 (e.g., 20.1), 21.1to 21.5 (e.g., 21.3), 21.9 to 22.3 (e.g., 22.1), and 23.0 to 23.4 (e.g.,23.2).

In some embodiments, crystalline Compound 1 can have an XRPD patternwith characteristic peaks between and including the following values of2θ in degrees: 11.6 to 12.0 (e.g., 11.8), 16.6 to 17.0 (e.g., 16.8),18.9 to 19.3 (e.g., 19.1), 19.9 to 20.3 (e.g., 20.1), and 23.0 to 23.4(e.g., 23.2).

In some embodiments, crystalline Compound 1 has an XRPD pattern withcharacteristic peaks at the following values of 2θ in degrees: 11.8,13.9, 14.2, 16.8, 19.1, 19.3, 20.1, 21.3, 22.1, and 23.2.

In some embodiments, crystalline Compound 1 has an XRPD pattern withcharacteristic peaks at the following values of 2θ in degrees: 11.8,16.8, 19.1, 20.1, and 23.2.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 10A.

In some embodiments, crystalline Compound 1 has an XRPD pattern withcharacteristic peaks between and including the following values of 2θ indegrees: 9.3 to 9.7 (e.g., 9.5), 10.6 to 11.0 (e.g., 10.8), 13.0 to 13.4(e.g., 13.2), 14.7 to 15.1 (e.g., 14.9), 15.8 to 16.2 (e.g., 16.0), 18.1to 18.5 (e.g., 18.3), 18.7 to 19.1 (e.g., 18.9), 20.9 to 21.3 (e.g.,21.1), 21.4 to 21.8 (e.g., 21.6), and 23.3 to 23.7 (e.g., 23.5).

In some embodiments, crystalline Compound 1 has an XRPD pattern withcharacteristic peaks between and including the following values of 2θ indegrees: 9.3 to 9.7 (e.g., 9.5), 10.6 to 11.0 (e.g., 10.8), 13.0 to 13.4(e.g., 13.2), 18.7 to 19.1 (e.g., 18.9), and 21.4 to 21.8 (e.g., 21.6).

In some embodiments, crystalline Compound 1 has an XRPD pattern withcharacteristic peaks at the following values of 2θ in degrees: 9.5,10.8, 13.2, 14.9, 16.0, 18.3, 18.9, 21.1, 21.6, and 23.5.

In some embodiments, crystalline Compound 1 has an XRPD pattern withcharacteristic peaks at the following values of 2θ in degrees: 9.5,10.8, 13.2, 18.9, and 21.6.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 1A.

In some embodiments, crystalline Compound 1 has comprises a unit cellsubstantially as depicted in FIG. 1B.

In some embodiments, a crystalline form of Compound 1, when subjected toa temperature from about 150° C. to about 195° C., e.g., from 157° C. to170° C., transforms into a different crystalline form as indicated byDSC at a ramp rate of 10° C./min.

In some embodiments, crystalline Compound 1 melts at a Toner from about200° C. to about 225° C., e.g., from about 205° C. to about 225° C.,e.g., from about 208° C. to about 215° C., as measured by DSC at a ramprate of 10° C./min.

In some embodiments, crystalline Compound 1 can have an XRPD patternwith characteristic peaks between and including the following values of2θ in degrees: 9.7 to 10.1 (e.g., 9.9), 11.6 to 12.0 (e.g., 11.8), 13.2to 13.6 (e.g., 13.4), 14.2 to 14.6 (e.g., 14.4), 14.6 to 15.0 (e.g.,14.8), 16.8 to 17.2 (e.g., 17.0), 20.5 to 20.9 (e.g., 20.7), 21.3 to21.7 (e.g., 21.5), 21.4 to 21.8 (e.g., 21.6), and 22.4 to 22.8 (e.g.,22.6).

In some embodiments, crystalline Compound 1 can have an XRPD patternwith characteristic peaks between and including the following values of2θ in degrees: 9.7 to 10.1 (e.g., 9.9), 14.6 to 15.0 (e.g., 14.8), 16.8to 17.2 (e.g., 17.0), 20.5 to 20.9 (e.g., 20.7), and 21.3 to 21.7 (e.g.,21.5).

In some embodiments, crystalline Compound 1 has an XRPD pattern withcharacteristic peaks at the following values of 2θ in degrees: 9.9,11.8, 13.4, 14.4, 14.8, 17.0, 20.7, 21.5, 21.6, and 22.6.

In some embodiments, crystalline Compound 1 has an XRPD pattern withcharacteristic peaks at the following values of 2θ in degrees: 9.9,14.8, 17.0, 20.7, and 21.5.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 3A.

In some embodiments, crystalline Compound 1 has comprises a unit cellsubstantially as depicted in FIG. 3B.

In some embodiments, a crystalline form of Compound 1, when subjected toa temperature from about 180° C. to about 200° C., e.g., from about 184°C. to about 200° C., e.g., from about 184° C. to about 190° C.,transforms into a different crystalline form as indicated by DSC at aramp rate of 10° C./min.

In some embodiments, crystalline Compound 1 melts at a Toner from about200° C. to about 225° C., e.g., from about 211° C. to about 215° C., asmeasured by DSC at a ramp rate of 10° C./min.

In some embodiments, crystalline Compound 1 has any of the XRPD patternssubstantially as depicted in FIG. 2B.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 4A.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 5.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 6A.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 7A.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 8A.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 9A.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 11A.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 12.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 13A.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as depicted in FIG. 14A.

In some embodiments, crystalline Compound 1 has an XRPD patternsubstantially as any of those depicted in FIG. 16.

In one aspect, the invention describes a method for transforming acrystalline compound having an XRPD pattern with characteristic peaks atthe following values of 2θ in degrees: 11.8, 16.8, 19.1, 20.1, and 23.2to a crystalline compound having an XRPD pattern with characteristicpeaks at the following values of 2θ in degrees: 9.5, 10.8, 13.2, 18.9,and 21.6, the method comprising crystallization from a solubilized formof Compound 1 or slurry conversion.

In some embodiments, the transformation is performed using ethyl acetateas a solvent at a temperature from about 50° C. to about 70° C., e.g.,from 60° C. to 65° C.

In some embodiments, the transformation is performed in the presence ofseed crystals of the crystalline compound having an XRPD pattern withcharacteristic peaks at the following values of 2θ in degrees: 9.5,10.8, 13.2, 18.9, and 21.6, at a loading from about 0.1% to about 5.0%,e.g. from 0.2% to 1.0%, of the total amount of Compound 1 present.

In one aspect, the present invention describes a pharmaceuticalcomposition comprising a crystalline form of Compound 1, and apharmaceutically acceptable excipient.

In one aspect, the present invention describes a method for treating aCNS-related disorder in a subject in need thereof, comprisingadministering to the subject an effective amount of Compound 1, e.g., acrystalline solid form of Compound 1 described herein, apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof.

In some embodiments, the CNS-related disorder is a sleep disorder, amood disorder, a schizophrenia spectrum disorder, a convulsive disorder,a disorder of memory and/or cognition, a movement disorder, apersonality disorder, autism spectrum disorder, pain, traumatic braininjury, a vascular disease, a substance abuse disorder and/or withdrawalsyndrome, or tinnitus.

In some embodiments, crystalline Compound 1 is administered orally,parenterally, intradermally, intrathecally, intramuscularly,subcutaneously, vaginally, as a buccal, sublingually, rectally, as atopical, inhalation, intranasal, or transdermally.

In some embodiments, crystalline Compound 1 is administered chronically.

In another aspect, provided herein is a method of treating aneurological disorder, a psychiatric disorder, a seizure disorder, aneuroinflammatory disorder, a glaucoma or metabolic disorder, a sensorydeficit disorder, in a subject in need thereof, comprising administeringto the subject an effective amount of Compound 1 or a pharmaceuticallyacceptable composition thereof.

In another aspect, provided herein, is a method of using Compound 1 or apharmaceutically acceptable composition thereof, as a neuroprotectant,comprising administering to a subject in need thereof an effectiveamount of Compound 1 or a pharmaceutically acceptable compositionthereof.

In another aspect, provided herein, is a method of using Compound 1 or apharmaceutically acceptable composition thereof, as an analgesic orother agent for pain control, comprising administering to a subject inneed thereof an effective amount of Compound 1 or a pharmaceuticallyacceptable composition thereof. In some embodiments, the compound orpharmaceutically acceptable composition is used as an analgesic or otheragent for pain control to treat inflammatory pain, neuropathic pain,fibromyalgia, or peripheral neuropathy.

As used herein, “XRPD” refers to X-ray powder diffraction. As usedherein, “VT-XRPD” refers to variable temperature-X-ray powderdiffraction. As used herein, “TGA” refers to thermogravimetric analysis.As used herein, DSC refers to differential scanning calorimetry. As usedherein, “NMR” refers to nuclear magnetic resonance. As used herein,“DVS” refers to dynamic vapor sorption. As used herein, “DCM” refers todichloromethane. As used herein, “EtOAc” refers to ethyl acetate. Asused herein, “MeOH” refers to methanol. As used herein, “MBTE” refers tomethyl tert-butyl ether. As used herein, “RH” refers to relativehumidity. As used herein, “RT” refers to room temperature.

As used herein, “crystalline” refers to a solid having a highly regularchemical structure, i.e., having long range structural order in thecrystal lattice. The molecules are arranged in a regular, periodicmanner in the 3-dimensional space of the lattice. In particular, acrystalline form may be produced as one or more single crystallineforms. For the purposes of this application, the terms “crystallineform”, “single crystalline form,” “crystalline solid form,” “solidform,” and “polymorph” are synonymous and used interchangably; the termsdistinguish between crystals that have different properties (e.g.,different XRPD patterns and/or different DSC scan results).

The term “substantially crystalline” refers to forms that may be atleast a particular weight percent crystalline. Particular weightpercentages are 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between70% and 100%. In certain embodiments, the particular weight percent ofcrystallinity is at least 90%. In certain other embodiments, theparticular weight percent of crystallinity is at least 95%. In someembodiments, Compound 1 can be a substantially crystalline sample of anyof the crystalline solid forms described herein (e.g., Forms, A, B, C,D, E, F, H, I, J, K, L, M, N, O, and P).

The term “substantially pure” relates to the composition of a specificcrystalline solid form of Compound 1 that may be at least a particularweight percent free of impurities and/or other solid forms ofCompound 1. Particular weight percentages are 70%, 75%, 80%, 85%, 90%,95%, 99%, or any percentage between 70% and 100%. In some embodiments,Compound 1 can be a substantially pure sample of any of the crystallinesolid forms described herein. (e.g., Forms, A, B, C, D, E, F, H, I, J,K, L, M, N, O, and P). In some embodiments, Compound 1 can besubstantially pure Form A. In some embodiments, Compound 1 can besubstantially pure Form B. In some embodiments, Compound 1 can besubstantially pure Form C. In some embodiments, Compound 1 can besubstantially pure Form D. In some embodiments, Compound 1 can besubstantially pure Form E. In some embodiments, Compound 1 can besubstantially pure Form F. In some embodiments, Compound 1 can besubstantially pure Form H. In some embodiments, Compound 1 can besubstantially pure Form I. In some embodiments, Compound 1 can besubstantially pure Form J. In some embodiments, Compound 1 can besubstantially pure Form K. In some embodiments, Compound 1 can besubstantially pure Form L. In some embodiments, Compound 1 can besubstantially pure Form M. In some embodiments, Compound 1 can besubstantially pure Form N. In some embodiments, Compound 1 can besubstantially pure Form O. In some embodiments, Compound 1 can besubstantially pure Form P.

As used herein, the term “anhydrous” or “anhydrate” when referring to acrystalline form of Compound 1 means that no solvent molecules,including those of water, form a portion of the unit cell of thecrystalline form. A sample of an anhydrous crystalline form maynonetheless contain solvent molecules that do not form part of the unitcell of the anhydrous crystalline form, e.g., as residual solventmolecule left behind from the production of the crystalline form. In apreferred embodiment, a solvent can make up 0.5% by weight of the totalcomposition of a sample of an anhydrous form. In a more preferredembodiment, a solvent can make up 0.2% by weight of the totalcomposition of a sample of an anhydrous form. In some embodiments, asample of an anhydrous crystalline form of Compound 1 contains nosolvent molecules, e.g., no detectable amount of solvent. The term“solvate” when referring to a crystalline form of Compound 1 means thatsolvent molecules, e.g., organic solvents and water, form a portion ofthe unit cell of the crystalline form. Solvates that contain water asthe solvent are also referred to herein as “hydrates.” The term“isomorphic” when referring to a crystalline form of Compound 1 meansthat the form can comprise different chemical constituents, e.g.,contain different solvent molecules in the unit cell, but have identicalXRPD patterns. Isomorphic crystalline forms are sometimes referred toherein as “isomorphs.”

A crystalline form of Compound 1 described herein, e.g., Form K, canmelt at a specific temperature or across a range of temperatures. Such aspecific temperature or range of temperatures can be represented by theonset temperature (T_(onset)) of the melting endotherm in thecrystalline form's DSC trace. In some embodiments, at such an onsettemperature, a sample of a crystalline form of Compound 1 melts andundergoes a concurrently occurring side-process, e.g., recrystallizationor chemical decomposition. In some embodiments, at such an onsettemperature, a crystalline form of Compound 1 melts in the absence ofother concurrently occurring processes.

The term “characteristic peaks” when referring to the peaks in an XRPDpattern of a crystalline form of Compound 1 refers to a collection ofcertain peaks whose of 2θ across a range of 0°-40° are, as a whole,uniquely assigned to one of the crystalline forms of Compound 1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts an exemplary XRPD pattern of Form A.

FIG. 1B depicts an exemplary unit cell of Form A along the b axis.

FIG. 1C depicts exemplary TGA (upper) and DSC (lower) curves of Form A.

FIG. 1D depicts an overlay of exemplary VT-XRPD patterns of Form A atselected temperatures, along with an exemplary XRPD pattern of Form K.

FIG. 1E depicts an exemplary DVS isotherm of Form A at 25° C.

FIG. 1F depicts an exemplary XRPD patterns of Form A before and after anexemplary DVS measurement at 25° C.

FIG. 2A depicts an exemplary XRPD pattern of an isomorph of Form B.

FIG. 2B depicts exemplary XRPD patterns of three isomorphs of Form B.

FIG. 2C depicts exemplary TGA (upper) and DSC (lower) curves of anisomorph of Form B.

FIG. 2D depicts an overlay of exemplary VT-XRPD patterns of an isomorphof Form B along with an exemplary XRPD pattern of Form K.

FIG. 2E depicts exemplary TGA curves of isomorphs of Form B.

FIG. 2F depicts exemplary DSC curves of isomorphs of Form B.

FIG. 2G depicts an exemplary ¹H NMR spectrum of an isomorph of Form Bdissolved in DMSO-d₆.

FIG. 2H depicts an exemplary ¹H NMR spectrum of an isomorph of Form Bdissolved in DMSO-d₆.

FIG. 2I depicts an exemplary ¹H NMR spectrum of an isomorph of Form Bdissolved in DMSO-d₆.

FIG. 3A depicts an exemplary XRPD pattern of Form C.

FIG. 3B depicts an exemplary unit cell of Form C along the b axis.

FIG. 3C depicts exemplary TGA (upper) and DSC (lower) curves of Form C.

FIG. 3D depicts an overlay of exemplary XRPD patterns of Form C atselected temperatures as well as an exemplary XRPD pattern of Form K.

FIG. 3E depicts an overlay of exemplary XRPD patterns of Form C atselected temperatures in the presence or absence of an N₂ atmosphere.

FIG. 3F depicts an exemplary DVS isotherm of Form C at 25° C.

FIG. 3G depicts an overlay of exemplary XRPD patterns of Form C beforeand after a DVS measurement at 25° C.

FIG. 4A depicts an exemplary XRPD pattern of Form D.

FIG. 4B depicts an overlay of exemplary XRPD patterns of Form D beforeand after drying at ambient conditions, along with an exemplary XRPDpattern of Form A.

FIG. 5 depicts an exemplary XRPD pattern of Form E.

FIG. 6A depicts an exemplary XRPD pattern of Form F.

FIG. 6B depicts exemplary TGA (upper) and DSC (lower) curves of Form F.

FIG. 6C depicts an overlay of exemplary XRPD patterns of Form F atselected temperatures along with an exemplary XRPD pattern of Form K.

FIG. 6D depicts an exemplary ¹H NMR spectrum of Form F dissolved inDMSO-d₆.

FIG. 7A depicts an exemplary XRPD pattern of Form H.

FIG. 7B depicts an overlay of exemplary XRPD patterns of Form H beforeand after drying at ambient conditions and an exemplary XRPD pattern ofForm A.

FIG. 8A depicts an exemplary XRPD pattern of Form I.

FIG. 8B depicts an overlay of exemplary XRPD patterns of Form I beforeand after drying at ambient conditions for 3 days along with an XRPDpattern of Form A.

FIG. 9A depicts an exemplary XRPD pattern of Form J.

FIG. 9B depicts an overlay of exemplary XRPD patterns of Form J beforeand after drying at ambient conditions for 3 days, along with an XRPDpattern of Form A.

FIG. 10A depicts an exemplary XRPD pattern of Form K.

FIG. 10B depicts exemplary TGA (upper) and DSC (lower) curves of Form K.

FIG. 10C depicts an exemplary DVS isotherm of Form K at 25° C.

FIG. 10D depicts an overlay of exemplary XRPD patterns of Form K beforeand after an exemplary DVS measurement at 25° C.

FIG. 11A depicts an exemplary XRPD pattern of Form L.

FIG. 11B depicts an overlay of exemplary XRPD patterns of Form L beforeand after 3 days, along with exemplary XRPD patterns of Form M and FormB.

FIG. 11C depicts an exemplary DSC curve of Form L.

FIG. 12 depicts an exemplary XRPD pattern of Form M.

FIG. 13A depicts an exemplary XRPD pattern of Form N.

FIG. 13B depicts an overlay of exemplary XRPD patterns of Form N beforeand after drying at ambient conditions overnight, along with anexemplary XRPD pattern of Form A.

FIG. 13C depicts exemplary TGA (upper) and DSC (lower) curves of Form N.

FIG. 13D depicts an exemplary ¹H NMR spectrum of Form N dissolved inDMSO-d₆.

FIG. 14A depicts an exemplary XRPD pattern of Form O.

FIG. 14B depicts exemplary TGA (upper) and DSC (lower) curves of Form O.

FIG. 14C depicts an overlay of exemplary XRPD patterns of Form O atselected temperatures along with an exemplary XRPD pattern of Form C.

FIG. 14D depicts an exemplary ¹H NMR spectrum of Form O dissolved inDMSO-d₆.

FIG. 15 depicts an overlay of exemplary XRPD patterns indicating thetime-dependent conversion of Form A to Form C in ethyl acetate at anelevated temperature in the presence of seed crystals of Form C.

FIG. 16 depicts exemplary XRPD patterns of Form P corresponding to wetsample (“Wet cake”), air dried sample at room temperature (“Air Dried”),and oven-dried sample at 40° C. (“Oven dried). An exemplary XRPD of areference sample of Form A is also provided.

FIG. 17A depicts an exemplary ¹H NMR spectrum of Form P after air-dryingat room temperature.

FIG. 17B depicts an exemplary ¹H NMR spectrum of Form P afteroven-drying at 40° C.

FIG. 18A depicts an exemplary TGA curve of Form P after air-drying atroom temperature.

FIG. 18B depicts an exemplary TGA curve of Form P after oven-drying at40° C.

FIG. 19. depicts an exemplary plot of solubility data of Forms A, C, andP in ethyl acetate.

FIG. 20. depicts an exemplary phase relationship between Forms A, C, andP.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

In one aspect, the present invention describes a compound of Formula(I), also referred to herein as “Compound 1,” has been found to exist asdifferent crystalline forms as indicated by various analytical methods.Compound 1 and its chemical synthesis are previously disclosed in U.S.Patent Application Publication No. US 20160083417 and PCT ApplicationPublication No. WO 2014169831. Exemplary individual solid forms of thepresent invention are provided in Table 1 below:

TABLE 1 Summary of exemplary Crystalline Forms of Compound 1. PolymorphForm A Form B Form C Form D Form E Form F Form H Form I Form J Form KForm L Form M Form N Form O Form PSolid Forms of Compound 1 Methods of Making the Same

Forms B, C, D, E, F, H, I, J, K, N, and O were prepared from Form Ausing various crystallization techniques described herein. Forms L and Mwere additionally prepared from Form B using other methods describedherein. These forms were subsequently characterized by one or more ofthe following analytical techniques: X-ray powder diffraction (XRPD),e.g., variable-temperature X-ray powder diffraction (VT-XRPD),thermogravimetric analysis (TGA), differential scanning calorimetry(DSC), or dynamic vapor sorption (DVS). The single-crystal structures,including the unit cells, of Form A and Form C were determined from dataobtained with an X-ray diffractometer. Furthermore, calculated XRPDpatterns for Form A and Form C were obtained using their single-crystalX-ray diffraction data. In the present invention, DSC and TGA data wereobtained using a ramp rate of 10° C./min.

Form A

Form A can be prepared by stirring crude Compound 1 as a slurry in ethylacetate below 10° C. and then filtering and drying under vacuum or bydissolving crude Compound 1 in dichloromethane and then re-concentratingthe solution twice with ethyl acetate under vacuum to dryness. Form Acan be determined to be a crystalline form of Compound 1 by XRPD. TGA,together with single-crystal structure of Form A, can be used toconclude that Form A is anhydrous. DSC can be used to indicate thepresence of two endotherms occurring at temperatures below 300° C.: oneendotherm with a Toner of 157.2° C. that represents the transformationof Form A into Form K, and another with a Toner of 203.8° C. thatrepresents the melting point of Form K. DVS can be used to demonstratethat Form A exhibits less than 0.30 weight percent water uptake at arelative humidity (RH) less than or equal to 95%.

In some embodiments, Form A can have an XRPD pattern substantially asdepicted in FIG. 1A. Additionally, representative peaks from the XRPDpattern of Form A can be indicated by their values of 20, d-spacing, andrelative intensities as, for example, in Table 2 below:

TABLE 2 Selected experimental XRPD pattern data for Form A. 2θ (degrees)d-spacing (Å) Relative Intensity (%) 9.494611 9.31518 40.49 10.788238.20093 46.5 13.22776 6.69345 37.69 14.89123 5.94927 10.18 15.993245.54174 15.09 18.28113 4.85302 31.96 18.93233 4.68754 100 21.052074.2201 10.38 21.64548 4.10573 24.16 23.50505 3.78495 15.37

In some embodiments, Form A has an XRPD pattern with characteristicpeaks between and including the following values of 2θ in degrees: 9.3to 9.7 (e.g., 9.5), 10.6 to 11.0 (e.g., 10.8), 13.0 to 13.4 (e.g.,13.2), 14.7 to 15.1 (e.g., 14.9), 15.8 to 16.2 (e.g., 16.0), 18.1 to18.5 (e.g., 18.3), 18.7 to 19.1 (e.g., 18.9), 20.9 to 21.3 (e.g., 21.1),21.4 to 21.8 (e.g., 21.6), and 23.3 to 23.7 (e.g., 23.5). In someembodiments, Form A has an XRPD pattern with characteristic peaksbetween and including the following values of 2θ in degrees: 9.3 to 9.7(e.g., 9.5), 10.6 to 11.0 (e.g., 10.8), 13.0 to 13.4 (e.g., 13.2), 18.7to 19.1 (e.g., 18.9), and 21.4 to 21.8 (e.g., 21.6). In someembodiments, Form A has an XRPD pattern with characteristic peaks at thefollowing values of 2θ in degrees: 9.5, 10.8, 13.2, 14.9, 16.0, 18.3,18.9, 21.1, 21.6, and 23.5. In some embodiments, Form A has an XRPDpattern with characteristic peaks at the following values of 2θ indegrees: 9.5, 10.8, 13.2, 18.9, and 21.6.

Calculated XRPD data for selected peaks can be obtained from X-raydiffraction data from a single crystal of Form A as provided in Table 3below, which complement the experimental data in Table 2.

TABLE 3 Selected calculated XRPD pattern data for Form A. 2θ (degrees)d-spacing (Å) Relative Intensity (%) 10.9265 8.09076 21.14 13.320976.64132 48.56 14.11329 6.27021 20.36 14.94619 5.92262 24.95 16.052325.5169 49.72 17.42404 5.08555 48.28 18.40825 4.81581 100 19.2493 4.6072518.47 24.23572 3.66943 19.02 24.3725 3.64915 19.56Form B

Form B can exist as a crystalline form of Compound 1 as determined byXRPD and can be prepared from various techniques described herein, e.g.,slow evaporation, slurry conversion, anti-solvent addition, solid vapordiffusion, or slow cooling. Furthermore, isomorphs of Form B fromdifferent solvent systems such as dichloromethane (DCM)/n-heptane,tetrahydrofuran (THF)/n-heptane, or chloroform (CHCl₃)/methyl tert-butylether (MBTE) can be prepared. Table 4 summarizes the properties of theseisomorphs as determined by various instrumental methods, e.g., TGA, DSC,and ¹H NMR spectroscopy.

TABLE 4 Summary of exemplary isomorphs of Form B TGA T_(onset) forCompound Solvent Crystallization Weight DSC 1:Solvent Type of IsomorphSystem Method Loss (%) Endotherm (° C.) (molar ratio) solvate Form B-1DCM/n- Slurry 5.7 to 8.5 87.2, 211.7 1:0.4 n- heptane conversion Heptanesolvate Form B-2 THF/n- Anti-solvent 4.6 to 8.5 85.4, 212.2 1:0.3 n-heptane addition Heptane solvate Form B-3 CHCl₃/ Anti-solvent 10.2 69.2,211.6 1:0.5 CHCl₃ MBTE addition solvateForm C

Form C is a crystalline anhydrate of Compound 1 as determined by XRPDand can be prepared from Form A using a slurry conversioncrystallization technique in isopropyl alcohol and isopropyl acetate at50° C. TGA and single-crystal X-ray crystallography can be used toconfirm the absence of solvent in Form C. DSC can be used to indicatetwo endotherms below 300° C.: a broad peak with a Toner of 183.8° C.corresponding to the transformation of Form C into Form K and a sharppeak with a Toner of 211.0° C. corresponding to the melting of Form K.DVS can be used to demonstrate that Form C exhibits less than 0.32weight percent water uptake at RH less than or equal to 95%.

In some embodiments, Form C can have an XRPD pattern substantially asdepicted in FIG. 3A. Additionally, representative peaks from the XRPDpattern of Form C can be indicated by their values of 20, d-spacing, andrelative intensities as, for example, in Table 5 below:

TABLE 5 Selected experimental XRPD pattern data for Form C. 2θ (degrees)d-spacing (Å) Relative Intensity (%) 22.60955 3.93279 26.76 20.656234.30006 27.84 13.36358 6.62573 28.42 14.81188 5.98097 33.78 21.500664.12963 36.7 21.54634 4.12439 36.94 9.889125 8.94443 41.85 11.790757.50579 65.73 14.41313 6.14552 65.89 16.99542 5.21715 100

In some embodiments, Form C can have an XRPD pattern with characteristicpeaks between and including the following values of 2θ in degrees: 9.7to 10.1 (e.g., 9.9), 11.6 to 12.0 (e.g., 11.8), 13.2 to 13.6 (e.g.,13.4), 14.2 to 14.6 (e.g., 14.4), 14.6 to 15.0 (e.g., 14.8), 16.8 to17.2 (e.g., 17.0), 20.5 to 20.9 (e.g., 20.7), 21.3 to 21.7 (e.g., 21.5),21.4 to 21.8 (e.g., 21.6), and 22.4 to 22.8 (e.g., 22.6). In someembodiments, Form C can have an XRPD pattern with characteristic peaksbetween and including the following values of 2θ in degrees: 9.7 to 10.1(e.g., 9.9), 14.6 to 15.0 (e.g., 14.8), 16.8 to 17.2 (e.g., 17.0), 20.5to 20.9 (e.g., 20.7), and 21.3 to 21.7 (e.g., 21.5). In someembodiments, Form C can have an XRPD pattern with characteristic peaksat the following values of 2θ in degrees: 9.9, 11.8, 13.4, 14.4, 14.8,17.0, 20.7, 21.5, 21.6, and 22.6. In some embodiments, Form C can havean XRPD pattern with characteristic peaks at the following values of 2θin degrees: 9.9, 14.8, 17.0, 20.7, and 21.5.

Calculated XRPD data for selected peaks can be obtained using X-raydiffraction data from a single crystal of Form C, as provided in Table 6below. These simulated peaks can complement the experimental data inTable 5.

TABLE 6 Selected calculated XRPD pattern data for Form C. 2θ (degrees)d-spacing (Å) Relative Intensity (%) 9.861923 8.96162 19.41 11.759597.51938 37.75 13.33554 6.6341 31.9 14.38478 6.15248 43.36 14.790215.98473 26.68 16.96659 5.22162 100 19.61234 4.52277 17.69 20.601234.30785 30.39 21.48653 4.13232 25.6 22.57956 3.93469 27.32Form D

Form D can be prepared using an anti-solvent addition crystallizationtechnique in tetrahydrofuran (THF)/water (H₂O) and, by XRPD analysis,can be subsequently found to be a crystalline form of Compound 1 thatconverted back to Form A upon drying at room temperature.

Form E

Form E can be prepared from an anti-solvent crystallization technique in1,4-dioxane/n-heptane at room temperature and can be determined to be acrystalline wet sample of Compound 1 by XRPD.

Form F

Form F can be prepared with an anti-solvent addition crystallizationtechnique in 1,4-dioxane/n-heptane at ambient room-temperatureconditions and determined to be a crystalline form of Compound 1 byXRPD. TGA on a sample of Form F exhibits a weight loss of 19.7% up to200° C. DSC can be used to show that Form F exhibits 2 endothermic peaksat onset temperatures of 63.1° C. and 210.7° C., corresponding to theloss of solvent (transformation to Form K) and the melting point of FormK, respectively. The transformation of Form F to Form K can beadditionally confirmed through VT-XRPD measurements. Based on ¹H NMRspectroscopy, Form F is a 1,4-dioxane solvate with a molar ratio of1:0.9 with residual n-heptane present.

Form H

Form H can be prepared from a solution vapor diffusion crystallizationtechnique in n-heptane at room temperature. The form was determined tobe crystalline by XRPD, but metastable due to its transformation to FormA after drying at ambient conditions for 3 days.

Form I

Form I can be made using a slow cooling crystallization techniqueperformed in methanol at room temperature. Like Form H, Form I can bedetermined to be a crystalline material by XRPD analysis, but was foundto be metastable due to its transformation to Form A after drying atambient conditions for 3 days.

Form J

Form J can be prepared using a solid vapor diffusion crystallizationtechnique in methanol at room temperature. XRPD analysis can be used toconclude that Form J is a crystalline metastable sample that transformsto Form A after drying at ambient conditions for 3 days.

Form K

Form K can be prepared by heating various forms of Compound 1, e.g.,Form A, Form B, Form C, Form E, and Form F, to elevated temperatures.The analyzed sample of this form can be determined to be crystalline byXRPD analysis. TGA can be used to indicate no weight loss prior to thedecomposition temperature and demonstrates that Form K is anhydrous. DSCcan be used to demonstrate that Form K can exhibit a single endothermwith a Toner of 211.6° C. that corresponds to the melting point of theanalyzed sample. DVS measurements were performed to demonstrate thatForm K demonstrates less than 0.35 weight percent water uptake at RHless than or equal to 95%.

In some embodiments, Form K can have an XRPD pattern substantially asdepicted in FIG. 10A. Additionally, representative peaks from the XRPDpattern of Form K can be indicated by their values of 2θ and relativeintensities as, for example, in Table 7 below:

TABLE 7 Selected experimental XRPD pattern data for Form K. 2θ (degrees)d-spacing (Å) Relative Intensity (%) 13.9471 6.3498 19.12 20.097674.41829 20.68 23.20826 3.83268 23.69 22.05504 4.0304 24.27 19.109054.64459 24.93 21.32362 4.16697 26.68 19.33614 4.59055 28.07 14.161256.25426 47 16.84678 5.26284 61.56 11.75077 7.53124 100

In some embodiments, Form K can have an XRPD pattern with characteristicpeaks between and including the following values of 2θ in degrees: 11.6to 12.0 (e.g., 11.8), 13.7 to 14.1 (e.g., 13.9), 14.0 to 14.4 (e.g.,14.2), 16.6 to 17.0 (e.g., 16.8), 18.9 to 19.3 (e.g., 19.1), 19.1 to19.5 (e.g., 19.3), 19.9 to 20.3 (e.g., 20.1), 21.1 to 21.5 (e.g., 21.3),21.9 to 22.3 (e.g., 22.1), and 23.0 to 23.4 (e.g., 23.2). In someembodiments, Form K can have an XRPD pattern with characteristic peaksbetween and including the following values of 2θ in degrees: 11.6 to12.0 (e.g., 11.8), 16.6 to 17.0 (e.g., 16.8), 18.9 to 19.3 (e.g., 19.1),19.9 to 20.3 (e.g., 20.1), and 23.0 to 23.4 (e.g., 23.2). In someembodiments, Form K can have an XRPD pattern with characteristic peaksat the following values of 2θ in degrees: 11.8, 13.9, 14.2, 16.8, 19.1,19.3, 20.1, 21.3, 22.1, and 23.2. In some embodiments, Form K can havean XRPD pattern with characteristic peaks at the following values of 2θin degrees: 11.8, 16.8, 19.1, 20.1, and 23.2.

Form L

Form L can be prepared by storing Form B in a sealed vial at ambientconditions for one month. This form can be determined to be acrystalline metastable form of Compound 1. Analysis with XRPD canindicate that Form L transforms to a mixture of Form B and Form M atambient conditions 3 days after preparation. Form L was determined to bea solvate of Compound 1.

Form M

Form M can be made by storing Form B in a sealed vial at ambientconditions for one month. The analyzed sample of this form wasdetermined to have low crystallinity by analysis with XRPD.

Form N

Form N can be prepared from a reverse anti-solvent additioncrystallization technique in 1,4-dioxane/n-heptane and determined to bea crystalline form of Compound 1 by XRPD. TGA can be used to determinethat Form N is a solvate that exhibits a weight loss of 2.5% up to 60°C., followed by a weight loss of 7.1% up to 200° C. DSC can be used todemonstrate two endotherms, one corresponding to the loss of solvent ata T_(onset) of 75.4° C. and the other at a T_(onset) of 210.4° C., whichrepresents the melting point of Form K. VT-XRPD can be used to confirmthat Form N transforms to Form K at 100° C. Based on ¹H NMRspectroscopy, Form N is a 1,4-dioxane solvate with a molar ratio of1:0.3 for Compound 1:1,4-dioxane.

Form O

Form O can be prepared using a water activity experiment in awater/acetonitrile mixture (0.041 water:0.959 acetonitrilevolume/volume; a_(w)=0.6) at room temperature and determined to be acrystalline form of Compound 1 by XRPD. TGA on a sample of Form O canindicate weight loss of 5.3% up to 55.1° C., followed by 5.9% up to 200°C. DSC can be used to show that Form O exhibits three endotherms, one atT_(onset)=65.0° C. corresponding to the loss of solvent to create FormC, one at T_(onset)=168.5° C. corresponding to transformation to Form Cto Form K, and one at T_(onset)=210.8° C. corresponding to melting ofForm K. Form O can be further characterized by ¹H NMR spectroscopydissolved in DMSO-d₆.

Form P

In addition the above-described forms, Form P is an ethyl acetate(EtOAc) solvate of Compound 1 and can be detected in (a) slurries ofForm A in EtOAc at 5° C. (after 1 h) and 20° C. (after 2 days), (b)slurries of Form C in EtOAc at 5° C. (after 1 h) and 20° C. (after 7days). The wet cake of Form P (˜5 min air) can be dried in two ways: (a)under air at room temperature overnight, and (b) under vacuum at 40° C.for 3 hours. Both dried cakes can be analyzed by XRPD, ¹H-NMR, and TGA.An air dried cake of Form P can give an XRPD pattern conforming to FormP, about 1% weight loss by TGA up to about 50° C., and EtOAc peaks by ¹HNMR. The sample of Form P post-oven drying, on the other hand, can givean XRPD pattern conforming to Form A, no weight loss ≤100° C. by TGA,and no EtOAc peaks by ¹H-NMR. Therefore, Form P can convert to Form Aupon drying.

In another aspect, the present invention provides a method fortransforming a solid form of Compound 1 or mixture of solid forms ofCompound 1 to a different anhydrate of Compound 1. In one embodiment,Form A, a mixture of Form A or Form K, or a mixture of Form A, Form C,and Form K can be converted to Form C through slurry conversion in ethylacetate, n-butanol, or methyl tert-butyl ether at room temperature orelevated temperatures, e.g., 50° C. or 65° C. In these 3 solventsystems, Form C is the only form remaining after slurry conversion,revealing that this solid form was more thermodynamically stable fromroom temperature to 50° C. when compared to Form A and Form K. Inanother embodiment, From C can be obtained through crystallization ofsolubilized Compound 1 (originally Form A) in ethyl acetate at anelevated temperature, e.g., 65° C., in the presence of a small amount,e.g. 0.2%-1.0%, of seed crystals of Form C, followed by cooling thebatch to a temperature no less than 25° C. to 30° C. Seed crystals ofForm C can be made using the procedure described in Example 4 describedherein.

Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a solid form of a compound of the present invention (alsoreferred to as the “active ingredient”) and a pharmaceuticallyacceptable excipient. In certain embodiments, the pharmaceuticalcomposition comprises an effective amount of the active ingredient. Incertain embodiments, the pharmaceutical composition comprises atherapeutically effective amount of the active ingredient. In certainembodiments, the pharmaceutical composition comprises a prophylacticallyeffective amount of the active ingredient.

The pharmaceutical compositions provided herein can be administered by avariety of routes including, but not limited to, oral (enteral)administration, parenteral (by injection) administration, rectaladministration, topical administration, transdermal administration,intradermal administration, intrathecal administration, subcutaneous(SC) administration, intramuscular (IM) administration,sublingual/buccal, ocular, otic, vaginal, and intranasal or inhalationadministration.

Generally, the solid forms of Compound 1 provided herein areadministered in an effective amount. The amount of the solid forms ofCompound 1 compound actually administered will typically be determinedby a physician, in the light of the relevant circumstances, includingthe condition to be treated, the chosen route of administration, theactual compound administered, the age, weight, and response of theindividual patient, the severity of the patient's symptoms, and thelike.

When used to prevent the onset of a CNS-disorder, the solid forms ofCompound 1 provided herein will be administered to a subject at risk fordeveloping the condition, typically on the advice and under thesupervision of a physician, at the dosage levels described above.Subjects at risk for developing a particular condition generally includethose that have a family history of the condition, or those who havebeen identified by genetic testing or screening to be particularlysusceptible to developing the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a solid form of Compound 1 or pharmaceuticalcomposition thereof over an extended period of time, e.g., for example,over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or maybe continued indefinitely, for example, for the rest of the subject'slife. In certain embodiments, the chronic administration is intended toprovide a consistent level of Compound 1 in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compositions of the present invention may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of Compound 1 in the blood toan effective level. The placement of the bolus dose depends on thesystemic levels of the active ingredient desired throughout the body,e.g., an intramuscular or subcutaneous bolus dose allows a slow releaseof the active ingredient. Furthermore, in still yet other embodiments,the pharmaceutical composition may be administered as first as a bolusdose, followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions or bulk powders. More commonly, however,the compositions are presented in unit dosage forms to facilitateaccurate dosing. The term “unit dosage forms” refers to physicallydiscrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, a solid form of Compound 1is usually a minor component (from about 0.1 to about 50% by weight orpreferably from about 1 to about 40% by weight) with the remainder beingvarious vehicles or excipients and processing aids helpful for formingthe desired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of asolid form of Compound 1 provided herein, with preferred doses eachproviding from about 0.1 to about 10 mg/kg, and especially about 0.2 toabout 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight of, e.g., the drugreservoir or drug-adhesive reservoir for the transdermal patch,preferably from about 0.1 to about 20% by weight, preferably from about0.1 to about 10% by weight, and more preferably from about 0.5 to about15% by weight.

Solid compositions may include, for example, any of the followingingredients, or a solid form of Compound 1 of a similar nature: binders,surfactants, diluents or fillers, buffering agents, antiadherents,glidants, hydrophilic or hydrophobic polymers, retardants, stabilizingagents or stabilizers, disintegrants or superdisintegrants, dispersants,antioxidants, antifoaming agents, fillers, flavors, colorants,lubricants, sorbents, preservatives, plasticizers, coatings, orsweeteners, or mixtures thereof. For example, the excipient orexcipients could be a binder such as microcrystalline cellulose,polyvinyl pyrrolidone, hydroxylpropyl cellulose, low viscosityhydroxypropylmethylcellulose, gum tragacanth or gelatin; a diluent suchas mannitol, microcrystalline cellulose, maltodextrin, starch orlactose, a disintegrating agent such as alginic acid, Primogel, sodiumstarch glycolate, sodium croscarmellose, crospovidone, or corn starch; alubricant such as magnesium stearate, sodium stearyl fumarate orglyceryl behenate; a glidant such as colloidal silicon dioxide; apreservative such as potassium sorbate or methyl paraben, asurfactant,such as sodium lauryl sulfate, sodium docusate, poysorbate 20,polysorbate 80, cetyl triethyl ammonium bromide, polyethyeleneoxide-polypropylene oxide copolymers, or Cremophor EL. an antioxidantsuch as butylhydroxy toluene, butyl hydroxyanisole, propyl gallate,ascorbic acid, tocopherol or tocopherol acetate, sodium sulphite, orsodium metabisulfite, a coating comprising one or more ofhydroxypropykmethylcellulose, polyvinyl alcohol, methacrylatecopolymers, cellulose acetate, hydroxypropylmethylcellulose acetatesuccinate, shellac and others, a sweetening agent such as sucrose,sucralose, acesulfame K, sodium aspartame or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring. Any ofthe well known pharmaceutical excipients may be incorporated in thedosage form and may be found in the FDA's Inactive Ingredients Guide,Remington: The Science and Practice of Pharmacy, Twenty-first Ed.,(Pharmaceutical Press, 2005); Handbook of Pharmaceutical Excipients,Sixth Ed. (Pharmaceutical Press, 2009) all of which are incorporated byreference.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as aointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration and stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein. Topical delivery compositionsof interest include liquid formulations, such as lotions (liquidscontaining insoluble material in the form of a suspension or emulsion,intended for external application, including spray lotions) and aqueoussolutions, semi-solid formulations, such as gels (colloids in which thedisperse phase has combined with the dispersion medium to produce asemisolid material, such as a jelly), creams (soft solids or thickliquids) and ointments (soft, unctuous preparations), and solidformulations, such as topical patches. As such, delivery vehiclecomponents of interest include, but are not limited to: emulsions of theoil-in-water (O/W) and the water in-oil (W/O) type, milk preparations,lotions, creams, ointments, gels, serum, powders, masks, packs, sprays,aerosols, sticks, and patches.

The solid forms of Compound 1 provided herein can also be administeredby a transdermal device. Accordingly, transdermal administration can beaccomplished using a patch either of the reservoir or membrane type, orof an adhesive matrix or other matrix variety. Delivery compositions ofinterest include liquid formulations, such as lotions (liquidscontaining insoluble material in the form of a suspension or emulsion,intended for external application, including spray lotions) and aqueoussolutions, semi-solid formulations, such as gels (colloids in which thedisperse phase has combined with the dispersion medium to produce asemisolid material, such as a jelly), creams (soft solids or thickliquids) and ointments (soft, unctuous preparations), and solidformulations, such as topical patches. As such, delivery vehiclecomponents of interest include, but are not limited to: emulsions of theoil-in-water (O/W) and the water in-oil (W/O) type, milk preparations,lotions, creams, ointments, gels, serum, powders, masks, packs, sprays,aerosols, sticks, and patches. For a transdermal patch, the active agentlayer includes one or more active agents, one of which is Compound I. Incertain embodiments, the matrix is an adhesive matrix. The matrix mayinclude polymeric materials. Suitable polymers for the adhesive matrixinclude, but are not limited to: polyurethanes, acrylates, styrenicblock copolymers, silicones, and the like. For example, the adhesivematrix may include, but is not limited to, an acrylate polymer,polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene,styrenic block polymers, combinations of thereof, and the like.Additional examples of adhesives are described in Satas, “AcrylicAdhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed.,pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, N.Y. (1989), thedisclosure of which is herein incorporated by reference.

In certain embodiments, the active agent layer includes a permeationenhancer. The permeation enhancer may include, but is not limited to thefollowing: aliphatic alcohols, such as but not limited to saturated orunsaturated higher alcohols having 12 to 22 carbon atoms, such as oleylalcohol and lauryl alcohol; fatty acids, such as but not limited tolinolic acid, oleic acid, linolenic acid, stearic acid, isostearic acidand palmitic acid; fatty acid esters, such as but not limited toisopropyl myristate, diisopropyl adipate, and isopropyl palmitate;alcohol amines, such as but not limited to triethanolamine,triethanolamine hydrochloride, and diisopropanolamine; polyhydricalcohol alkyl ethers, such as but not limited to alkyl ethers ofpolyhydric alcohols such as glycerol, ethylene glycol, propylene glycol,1,3-butylene glycol, diglycerol, polyglycerol, diethylene glycol,polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan,sorbitol, isosorbide, methyl glucoside, oligosaccharides, and reducingoligosaccharides, where the number of carbon atoms of the alkyl groupmoiety in the polyhydric alcohol alkyl ethers is preferably 6 to 20;polyoxyethylene alkyl ethers, such as but not limited to polyoxyethylenealkyl ethers in which the number of carbon atoms of the alkyl groupmoiety is 6 to 20, and the number of repeating units (e.g. —OCH₂CH₂—) ofthe polyoxyethylene chain is 1 to 9, such as but not limited topolyoxyethylene lauryl ether, polyoxyethylene cetyl ether,polyoxyethylene stearyl ether, and polyoxyethylene oleyl ether;glycerides (i.e., fatty acid esters of glycerol), such as but notlimited to glycerol esters of fatty acids having 6 to 18 carbon atoms,diglycerides, triglycerides or combinations thereof. In someembodiments, the polymer matrix includes a polyvinylpyrrolidone. Thecomposition may further include one or more fillers or one or moreantioxidants. In some embodiments, the transdermal formulationsdescribed may have a multi-layer structure. For example, the transdermalformulation may have an adhesive matrix and a backing.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

A solid form of Compound 1 of the present invention can also beadministered in sustained release forms or from sustained release drugdelivery systems. A description of representative sustained releasematerials can be found in Remington's Pharmaceutical Sciences.

Methods of Use

Provided herein are methods of treating a disorder, e.g., a CNS-relateddisorder, in a subject in need thereof, comprising administering to thesubject an effective amount of the compound of Formula (I), e.g.,Compound 1 as a solid form described herein, or a pharmaceuticallyacceptable salt or pharmaceutically acceptable composition thereof. Incertain embodiments, the disorder is a CNS-related disorder selectedfrom the group consisting of a sleep disorder, a mood disorder, aschizophrenia spectrum disorder, a convulsive disorder, a disorder ofmemory and/or cognition, a movement disorder, a personality disorder,autism spectrum disorder, pain, traumatic brain injury, a vasculardisease, a substance abuse disorder and/or withdrawal syndrome, andtinnitus. In some embodiments, the disorder is a comorbid disorder(e.g., depression comorbid with a personality disorder or a sleepdisorder comorbid with a personality disorder). In some embodiments, thedisorder is a neurological disorder as described herein. In someembodiments, the disorder is a neurological disorder as describedherein. In some embodiments, the disorder is a psychiatric disorder asdescribed herein. In some embodiments, the disorder is a seizuredisorder as described herein. In some embodiments, the disorder is aneuroinflammatory disorder as described herein. In some embodiments, thedisorder is a glaucoma or metabolic disorder as described herein. Insome embodiments, the disorder is a sensory deficit disorder asdescribed herein. Also provided herein are methods of using Compound 1,e.g., Compound 1 as a solid form described herein, or a pharmaceuticallyacceptable salt or pharmaceutical composition thereof, as aneuroprotectant. Also provided herein are methods of using Compound 1,e.g., Compound 1 as a solid form described herein, or a pharmaceuticallyacceptable salt or pharmaceutical composition thereof, as an analgesicor other agent for pain control.

Neurological Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a disorder described herein such as aneurological disorder. Exemplary neurological disorders include, but arenot limited to, neurodegenerative disorders, neurodevelopmentaldisorders, neuroendocrine disorders and dysfunction, movement disorders,and sleep disorders as described herein.

Neurodegenerative Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a neurodegenerative disorder.

The term “neurodegenerative disease” includes diseases and disordersthat are associated with the progressive loss of structure or functionof neurons, or death of neurons. Neurodegenerative diseases anddisorders include, but are not limited to, Alzheimer's disease(including the associated symptoms of mild, moderate, or severecognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic andischemic injuries; benign forgetfulness; brain edema; cerebellar ataxiaincluding McLeod neuroacanthocytosis syndrome (MLS); closed head injury;coma; contusive injuries (e.g., spinal cord injury and head injury);dementias including multi-infarct dementia and senile dementia;disturbances of consciousness; Down syndrome; fragile X syndrome; Gillesde la Tourette's syndrome; head trauma; hearing impairment and loss;Huntington's disease; Lennox syndrome; mental retardation; neuronaldamage including ocular damage, retinopathy or macular degeneration ofthe eye; neurotoxic injury which follows cerebral stroke, thromboembolicstroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm,hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiacarrest; Parkinson's disease; stroke; tinnitus; tubular sclerosis, andviral infection induced neurodegeneration (e.g., caused by acquiredimmunodeficiency syndrome (AIDS) and encephalopathies).Neurodegenerative diseases also include, but are not limited to,neurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia,amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methodsof treating or preventing a neurodegenerative disease also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Neurodevelopmental Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a disorder described herein such as aneurodevelopmental disorder. In some embodiments, the neurodevelopmentaldisorders is autism spectrum disorder. In some embodiments, theneurodevelopmental disorder is Smith-Lemli-Opitz syndrome.

Neuroendocrine Disorders

Provided herein are methods that can be used for treating neuroendocrinedisorders and dysfunction. As used herein, “neuroendocrine disorder” or“neuroendocrine dysfunction” refers to a variety of conditions caused byimbalances in the body's hormone production directly related to thebrain. Neuroendocrine disorders involve interactions between the nervoussystem and the endocrine system. Because the hypothalamus and thepituitary gland are two areas of the brain that regulate the productionof hormones, damage to the hypothalamus or pituitary gland, e.g., bytraumatic brain injury, may impact the production of hormones and otherneuroendocrine functions of the brain. In some embodiments, theneuroendocrine disorder or dysfunction is associated with a women'shealth disorder or condition (e.g., a women's health disorder orcondition described herein). In some embodiments, the neuroendocrinedisorder or dysfunction is associated with a women's health disorder orcondition is polycystic ovary syndrome.

Symptoms of neuroendocrine disorder include, but are not limited to,behavioral, emotional, and sleep-related symptoms, symptoms related toreproductive function, and somatic symptoms; including but not limitedto fatigue, poor memory, anxiety, depression, weight gain or loss,emotional lability, lack of concentration, attention difficulties, lossof libido, infertility, amenorrhea, loss of muscle mass, increased bellybody fat, low blood pressure, reduced heart rate, hair loss, anemia,constipation, cold intolerance, and dry skin.

Movement Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a movement disorder. In some embodiments,the movement disorder is essential Tremor, Stiff-Person syndrome,spasticity, Freidrich's ataxia, Cerebellar ataxia, dystonia, TouretteSyndrome, Fragile X-associated tremor or ataxia syndromes, drug-inducedor medication-induced Parkinsonism (such as neuroleptic-induced acuteakathisia, acute dystonia, Parkinsonism, or tardive dyskinesia,neuroleptic malignant syndrome, or medication-induced postural tremor),ataxia, cerebellar ataxia including McLeod neuroacanthocytosis syndrome(MLS), levodopa-induced dyskinesia, movement disorders includingakinesias and akinetic (rigid) syndromes (including basal gangliacalcification, corticobasal degeneration, multiple system atrophy,Parkinsonism-ALS dementia complex, Parkinson's disease, postencephaliticparkinsonism, and progressively supranuclear palsy); muscular spasms anddisorders associated with muscular spasticity or weakness includingchorea (such as benign hereditary chorea, drug-induced chorea,hemiballism, Huntington's disease, neuroacanthocytosis, Sydenham'schorea, and symptomatic chorea), dyskinesia (including tics such ascomplex tics, simple tics, and symptomatic tics), myoclonus (includinggeneralized myoclonus and focal cyloclonus), tremor (such as resttremor, postural tremor, and intention tremor), or dystonia (includingaxial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, and spasmodic dysphonia and torticollis).

As used herein, “movement disorders” refers to a variety of diseases anddisorders that are associated with hyperkinetic movement disorders andrelated abnormalities in muscle control. Exemplary movement disordersinclude, but are not limited to, Parkinson's disease and parkinsonism(defined particularly by bradykinesia), dystonia, chorea andHuntington's disease, ataxia, tremor (e.g., essential tremor), myoclonusand startle, tics and Tourette syndrome, Restless legs syndrome, stiffperson syndrome, and gait disorders. Exemplary movement disordersinclude, but are not limited to, Parkinson's disease and parkinsonism(defined particularly by bradykinesia), dystonia, chorea andHuntington's disease, ataxia, tremor (e.g., essential tremor), myoclonusand startle, tics and Tourette syndrome, Restless legs syndrome, stiffperson syndrome, and gait disorders.

Tremor

The methods described herein can be used to treat tremor, for example,the compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used to treat cerebellar tremor or intentiontremor, dystonic tremor, essential tremor, orthostatic tremor,parkinsonian tremor, physiological tremor, psychogenic tremor, or rubraltremor. Tremor includes hereditary, degenerative, and idiopathicdisorders such as Wilson's disease, Parkinson's disease, and essentialtremor, respectively; metabolic diseases (e.g., thyoid-parathyroid-,liver disease and hypoglycemia); peripheral neuropathies (associatedwith Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complexregional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese,arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium,cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine,steroids, valproate, amiodarone, thyroid hormones, vincristine); andpsychogenic disorders. Clinical tremor can be classified intophysiologic tremor, enhanced physiologic tremor, essential tremorsyndromes (including classical essential tremor, primary orthostatictremor, and task- and position-specific tremor), dystonic tremor,parkinsonian tremor, cerebellar tremor, Holmes' tremor (i.e., rubraltremor), palatal tremor, neuropathic tremor, toxic or drug-inducedtremor, and psychogenic tremor.

Tremor is an involuntary, at times rhythmic, muscle contraction andrelaxation that can involve oscillations or twitching of one or morebody parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk,legs).

Cerebellar tremor or intention tremor is a slow, broad tremor of theextremities that occurs after a purposeful movement. Cerebellar tremoris caused by lesions in or damage to the cerebellum resulting from,e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inheriteddegenerative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movementdisorder in which sustained involuntary muscle contractions causetwisting and repetitive motions and/or painful and abnormal postures orpositions. Dystonic tremor may affect any muscle in the body. Dystonictremors occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type oftremor. Essential tremor may be mild and nonprogressive in some, and maybe slowly progressive, starting on one side of the body but affect bothsides within 3 years. The hands are most often affected, but the head,voice, tongue, legs, and trunk may also be involved. Tremor frequencymay decrease as the person ages, but severity may increase. Heightenedemotion, stress, fever, physical exhaustion, or low blood sugar maytrigger tremors and/or increase their severity. Symptoms generallyevolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz)rhythmic muscle contractions that occurs in the legs and trunkimmediately after standing. Cramps are felt in the thighs and legs andthe patient may shake uncontrollably when asked to stand in one spot.Orthostatic tremor may occurs in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brainthat control movement. Parkinsonian tremor is often a precursor toParkinson's disease and is typically seen as a “pill-rolling” action ofthe hands that may also affect the chin, lips, legs, and trunk. Onset ofparkinsonian tremor typically begins after age 60. Movement starts inone limb or on one side of the body and can progress to include theother side.

Physiological tremor can occur in normal individuals and have noclinical significance. It can be seen in all voluntary muscle groups.Physiological tremor can be caused by certain drugs, alcohol withdrawal,or medical conditions including an overactive thyroid and hypoglycemia.The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or duringpostural or kinetic movement. Patient with psychogenic tremor may have aconversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can bepresent at rest, at posture, and with intention. The tremor isassociated with conditions that affect the red nucleus in the midbrain,classical unusual strokes.

Parkinson's Disease affects nerve cells in the brain that producedopamine. Symptoms include muscle rigidity, tremors, and changes inspeech and gait. Parkinsonism is characterized by tremor, bradykinesia,rigidity, and postural instability. Parkinsonism shares symptoms foundin Parkinson's Disease, but is a symptom complex rather than aprogressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained orintermittent muscle contractions causing abnormal, often repetitivemovements or postures. Dystonic movements can be patterned, twisting,and may be tremulous. Dystonia is often initiated or worsened byvoluntary action and associated with overflow muscle activation.

Chorea is a neurological disorder characterized by jerky involuntarymovements typically affecting the shoulders, hips, and face.Huntington's Disease is an inherited disease that causes nerve cells inthe brain to waste away. Symptoms include uncontrolled movements,clumsiness, and balance problems. Huntington's disease can hinder walk,talk, and swallowing.

Ataxia refers to the loss of full control of bodily movements, and mayaffect the fingers, hands, arms, legs, body, speech, and eye movements.

Myloclonus and Startle is a response to a sudden and unexpectedstimulus, which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief,repetitive, but non-rhythmical, typically imitating normal behavior andoften occurring out of a background of normal activity. Tics can beclassified as motor or vocal, motor tics associated with movements whilevocal tics associated with sound. Tics can be characterized as simple orcomplex. For example simple motor tics involve only a few musclesrestricted to a specific body part.

Tourette Syndrome is an inherited neuropsychiatric disorder with onsetin childhood, characterized by multiple motor tics and at least onevocal tic.

Restless Legs Syndrome is a neurologic sensorimotor disordercharacterized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movement disorder characterizedby involuntary painful spasms and rigidity of muscles, usually involvingthe lower back and legs. Stiff-legged gait with exaggerated lumbarhyperlordosis typically results. Characteristic abnormality on EMGrecordings with continuous motor unit activity of the paraspinal axialmuscles is typically observed. Variants include “stiff-limb syndrome”producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormalitiy in the manner or style ofwalking, which results from neuromuscular, arthritic, or other bodychanges. Gait is classified according to the system responsible forabnormal locomotion, and include hemiplegic gait, diplegic gait,neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait,ataxic gait, and sensory gait.

Sleep Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a sleep disorder. In some embodiments, thesleep disorder is comorbid with another disorder (e.g., a sleep disordercomorbid with a personality disorder).

Psychiatric Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a disorder described herein such as apsychiatric disorder. Exemplary psychiatric disorders include, but arenot limited to, mood disorders, anxiety disorders, psychotic disorders,and impulse control disorders as described herein.

Mood Disorders

Also provided herein are methods for treating a mood disorder, forexample, clinical depression, postnatal depression or postpartumdepression, perinatal depression, atypical depression, melancholicdepression, psychotic major depression, catatonic depression, seasonalaffective disorder, dysthymia, double depression, depressive personalitydisorder, recurrent brief depression, minor depressive disorder, bipolardisorder or manic depressive disorder, depression caused by chronicmedical conditions, comorbid depression, treatment-resistant depression,refractory depression, suicidality, suicidal ideation, or suicidalbehavior. In some embodiments, the method described herein providestherapeutic effect to a subject suffering from depression (e.g.,moderate or severe depression). In some embodiments, the mood disorderis associated with a disease or disorder described herein (e.g.,neuroendocrine diseases and disorders, neurodegenerative diseases anddisorders (e.g., epilepsy), movement disorders, tremor (e.g.,Parkinson's Disease), women's health disorders or conditions).

Clinical depression is also known as major depression, major depressivedisorder (MDD), severe depression, unipolar depression, unipolardisorder, and recurrent depression, and refers to a mental disordercharacterized by pervasive and persistent low mood that is accompaniedby low self-esteem and loss of interest or pleasure in normallyenjoyable activities. Some people with clinical depression have troublesleeping, lose weight, and generally feel agitated and irritable.Clinical depression affects how an individual feels, thinks, and behavesand may lead to a variety of emotional and physical problems.Individuals with clinical depression may have trouble doing day-to-dayactivities and make an individual feel as if life is not worth living.

Peripartum depression refers to depression in pregnancy. Symptomsinclude irritability, crying, feeling restless, trouble sleeping,extreme exhaustion (emotional and/or physical), changes in appetite,difficulty focusing, increased anxiety and/or worry, disconnectedfeeling from baby and/or fetus, and losing interest in formerlypleasurable activities.

Postnatal depression (PND) is also referred to as postpartum depression(PPD), and refers to a type of clinical depression that affects womenafter childbirth. Symptoms can include sadness, fatigue, changes insleeping and eating habits, reduced sexual desire, crying episodes,anxiety, and irritability. In some embodiments, the PND is atreatment-resistant depression (e.g., a treatment-resistant depressionas described herein). In some embodiments, the PND is refractorydepression (e.g., a refractory depression as described herein).

In some embodiments, a subject having PND also experienced depression,or a symptom of depression during pregnancy. This depression is referredto herein as) perinatal depression. In an embodiment, a subjectexperiencing perinatal depression is at increased risk of experiencingPND.

Atypical depression (AD) is characterized by mood reactivity (e.g.,paradoxical anhedonia) and positivity, significant weight gain orincreased appetite. Patients suffering from AD also may have excessivesleep or somnolence (hypersomnia), a sensation of limb heaviness, andsignificant social impairment as a consequence of hypersensitivity toperceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia)in most or all activities, failures to react to pleasurable stimuli,depressed mood more pronounced than that of grief or loss, excessiveweight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to amajor depressive episode, in particular of melancholic nature, where theindividual experiences psychotic symptoms such as delusions andhallucinations.

Catatonic depression refers to major depression involving disturbancesof motor behavior and other symptoms. An individual may become mute andstuporous, and either is immobile or exhibits purposeless or bizarremovements.

Seasonal affective disorder (SAD) refers to a type of seasonaldepression wherein an individual has seasonal patterns of depressiveepisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar depression, wherethe same physical and cognitive problems are evident. They are not assevere and tend to last longer (e.g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lastsfor at least 2 years and is punctuated by periods of major depression.

Depressive Personality Disorder (DPD) refers to a personality disorderwith depressive features.

Recurrent Brief Depression (RBD) refers to a condition in whichindividuals have depressive episodes about once per month, each episodelasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a depression inwhich at least 2 symptoms are present for 2 weeks.

Depression caused by chronic medical conditions refers to depressioncaused by chronic medical conditions such as cancer or chronic pain,chemotherapy, chronic stress.

Treatment-resistant depression refers to a condition where theindividuals have been treated for depression, but the symptoms do notimprove. For example, antidepressants or psychological counseling(psychotherapy) do not ease depression symptoms for individuals withtreatment-resistant depression. In some cases, individuals withtreatment-resistant depression improve symptoms, but come back.Refractory depression occurs in patients suffering from depression whoare resistant to standard pharmacological treatments, includingtricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs, as well as non-pharmacologicaltreatments (e.g., psychotherapy, electroconvulsive therapy, vagus nervestimulation and/or transcranial magnetic stimulation).

Post-surgical depression refers to feelings of depression that follow asurgical procedure (e.g., as a result of having to confront one'smortality). For example, individuals may feel sadness or empty moodpersistently, a loss of pleasure or interest in hobbies and activitiesnormally enjoyed, or a persistent felling of worthlessness orhopelessness. Mood disorder associated with conditions or disorders ofwomen's health refers to mood disorders (e.g., depression) associatedwith (e.g., resulting from) a condition or disorder of women's health(e.g., as described herein).

Suicidality, suicidal ideation, suicidal behavior refers to the tendencyof an individual to commit suicide. Suicidal ideation concerns thoughtsabout or an unusual preoccupation with suicide. The range of suicidalideation varies greatly, from e.g., fleeting thoughts to extensivethoughts, detailed planning, role playing, incomplete attempts. Symptomsinclude talking about suicide, getting the means to commit suicide,withdrawing from social contact, being preoccupied with death, feelingtrapped or hopeless about a situation, increasing use of alcohol ordrugs, doing risky or self-destructive things, saying goodbye to peopleas if they won't be seen again.

Depression or personality disorders may also be comorbid with anotherdisorder. For example, depression may be comorbid with a personalitydisorder. In another example, a personality disorder may be comorbidwith a sleep disorder.

Symptoms of depression include persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, difficulty sleeping, sleeplessness, irritability,fatigue, motor challenges, loss of interest in pleasurable activities orhobbies, loss of concentration, loss of energy, poor self-esteem,absence of positive thoughts or plans, excessive sleeping, overeating,appetite loss, insomnia, self-harm, thoughts of suicide, and suicideattempts. The presence, severity, frequency, and duration of symptomsmay vary on a case to case basis. Symptoms of depression, and relief ofthe same, may be ascertained by a physician or psychologist (e.g., by amental state examination).

Anxiety Disorders

Provided herein are methods for treating anxiety disorders (e.g.,generalized anxiety disorder, panic disorder, obsessive compulsivedisorder, phobia, post-traumatic stress disorder). Anxiety disorder is ablanket term covering several different forms of abnormal andpathological fear and anxiety. Current psychiatric diagnostic criteriarecognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Psychotic Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a psychotic disorder. In some embodiments,the impulse control disorder is schizophrenia or bipolar disorder. Insome embodiments, the psychotic disorder is schizophrenia. In someembodiments, the psychotic disorder is bipolar disorder.

Bipolar disorder or manic depressive disorder causes extreme mood swingsthat include emotional highs (mania or hypomania) and lows (depression).

Impulse Control Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of an impulse control disorder. In someembodiments, the impulse control disorder is anorexia nervosa or alcoholwithdrawal. In some embodiments, the impulse control disorder isanorexia nervosa. In some embodiments, the impulse control disorder isanorexia nervosa.

Seizure Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a seizure disorder. In some embodiments, theseizure disorder is epilepsy. In some embodiments, the seizure disorderis status epilepticus, e.g., convulsive status epilepticus, e.g., earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, or super-refractory status epilepticus. In someembodiments, the seizure disorder is a focal seizure with either motor(automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic,and tonic) or non-motor (autonomic, behavioral arrest, cognition,emotional, and sensory) onset, a generalized seizure with either motor(tonic-clonic, clonic, myoclonic, myoclonic-tonic-clonic,myoclonic-atonic, atonic, epileptic spasms) or non-motor (absence)onset, a seizure with unknown motor (tonic-clonic, epileptic spasms) ornon-motor (behavioral arrest) onset, a seizure associated with clinicalsyndromes, such as Dravet syndrome, Rett syndrome, Lennox Gasteausyndrome, Tuberous sclerosis, Angelmans syndrome, catamenial epilepsy.In some embodiments, the seizure disorder is a seizure that is caused byschizoaffective disorder or by drugs used to treat schizophrenia.

Epilepsy

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Status Epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, or super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.”

Myoclonic seizures consist of sporadic jerks, usually on both sides ofthe body. Patients sometimes describe the jerks as brief electricalshocks. When violent, these seizures may result in dropping orinvoluntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures; recurrent seizures; status epilepticusseizures, e.g., refractory convulsive status epilepticus, non-convulsivestatus epilepticus seizures; refractory seizures; myoclonic seizures;tonic seizures; tonic-clonic seizures; simple partial seizures; complexpartial seizures; secondarily generalized seizures; atypical absenceseizures; absence seizures; atonic seizures; benign Rolandic seizures;febrile seizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures; infantile spasms; Jacksonian seizures;massive bilateral myoclonus seizures; multifocal seizures; neonatalonset seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; subtle seizures; Sylvan seizures; visual reflexseizures; or withdrawal seizures. In some embodiments, the seizure is ageneralized seizure associated with Dravet Syndrome, Lennox-GastautSyndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 FemalePediatric Epilepsy.

Neuroinflammatory Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a disorder described herein such as aneuroinflammatory disorder. In some embodiments, the neuroinflammatorydisorder is multiple sclerosis or a pediatric autoimmuneneuropsychiatric disorder associated with a streptococcal infection(PANDAS).

Analgesia/Pain Control

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample as an analgesic or other agent for pain control. In someembodiments, a solid form of Compound 1, or a pharmaceuticallyacceptable composition thereof, can be used as an analgesic or otheragent for pain control to treat inflammatory pain, neuropathic pain,fibromyalgia, or peripheral neuropathy.

Sensory Deficit Disorders

The compound of Formula (I), e.g., a solid form of Compound 1, or apharmaceutically acceptable salt or pharmaceutically acceptablecomposition thereof, can be used in a method described herein, forexample in the treatment of a disorder described herein such as asensory deficit disorder. In some embodiments, the sensory deficitdisorder is tinnitus or synesthesia. In some embodiments, the sensorydeficit disorder is hearing impairment and/or loss.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The examples describedin this application are offered to illustrate the crystalline solidforms provided herein and are not to be construed in any way as limitingtheir scope.

Example 1. Preparation of Solid Form A

Form A was prepared by stirring crude Compound 1 as a slurry in ethylacetate below 10° C. and then filtering and drying under vacuum. It wasalso formed by dissolving crude Compound 1 in dichloromethane and thenre-concentrating the solution twice with ethyl acetate under vacuum todryness.

Example 2. Various Wet Methods of Crystallization to Obtain Other SolidForms of the Present Invention

To find new crystalline forms, different crystallization methods wereevaluated using Form A as the starting material. In addition to Form A,thirteen crystalline forms (B, C, D, E, F, H, I, J, K, L, M, N, and O)were identified with these methods.

Slow Evaporation

Slow evaporation crystallization experiments were performed across 8different solvent systems. In each experiment approximately 10 mg ofForm A was dissolved in 0.4 to 1.0 mL of solvent in a 1.5 glass vial.The glass vials were sealed using PARAFILM® paraffin film pierced with 3to 5 holes to allow for solvent evaporation.

Slurry Conversion

In each experiment, approximately 10 to 20 mg of Form A was suspended in0.5 mL of a solvent or mixture of solvents. After stirring at RT or 50°C. for 48 hours, the solids were isolated by centrifugation for analysis(wet sample). If the suspensions turned into clear solution, the clearsolutions were kept at ambient conditions for slow evaporation.

Anti-Solvent Addition

In each experiment, approximately 10 mg of Form A was dissolved in 0.1to 1 mL of each solvent to obtain a clear solution. The anti-solvent wasadded in increments of 50 μL until precipitation was observed, or thetotal volume of anti-solvent reached 20 times that of the solventvolume. The precipitate was then isolated by centrifugation for analysis(wet sample). In the instances that clear solutions were observed, slowevaporation experiments were performed.

Slow-Cooling

In each experiment, approximately 10 mg of Form A was suspended in 0.8to 1.0 mL of each solvent mixture at 50° C. The resulting suspensionswere immediately filtered with a 0.2 μm filter, and the filtrates werecollected and cooled from 50° C. to 5° C. at a rate of 0.1° C./min. Theprecipitates were then isolated by centrifugation at 10,000 rpm for 3 to5 minutes for analysis (wet sample).

Solution Vapor Diffusion

In each experiment, approximately 10 mg of Form A was dissolved in anappropriate solvent to obtain a clear solution in a 3-mL glass vial. Thevial was then placed into a 20-mL glass vial containing 3 mL of theanti-solvent and sealed. The system was kept at RT for 7 days, allowingsufficient time for solid precipitation. The solids were isolated bycentrifugation at 10,000 rpm for 3 to 5 minutes and analyzed (wetsample). In the cases where no precipitation was observed, the sampleswere kept at ambient conditions for slow evaporation.

Solid Vapor Diffusion

In each experiment, approximately 10 mg of Form A was placed into a 3-mLglass vial, which was then sealed into a 20-mL glass vial containing 3mL of the specific solvent. The system was kept at RT for 7 days,allowing sufficient time for organic vapor to interact with the solids.The solids were then analyzed (wet sample).

Fast Evaporation

In each experiment, approximately 10 mg of Form A was dissolved in 0.5to 1.0 mL of each solvent in a 1.5-mL glass vial. The visually clearsolutions were kept at ambient conditions for fast evaporation with thelid off. The solids obtained via evaporation were then analyzed (drysample).

Reverse Anti-Solvent Addition

In each experiment, approximately 20 mg of Form A was dissolved in 0.2to 0.6 mL of each solvent to obtain a clear solution. The solution wasadded to a glass vial containing 2.0 mL of each anti-solvent at RTconditions. The precipitate formed was centrifuged at 10,000 rpm for 3to 5 minutes for analysis (wet sample). In the cases where noprecipitation was observed, slow evaporation experiments were conductedfor the remaining solutions.

Water Activity Experiments

Water activity experiments, ranging from 0 to 1 water activity (a_(w))at 0.2 intervals, were performed with H₂O and acetonitrile. About 10 mgof Form A was weighed into 1.5 mL vials and 0.5 mL of the solventmixture was added. The suspension was stirred at a rate of 1000 rpm atroom temperature. The residual solvent was removed from the sample bycentrifugation (10000 rpm for 3 min).

Example 3. Preparation of Solid Form B

Form B was prepared via slow evaporation, slurry conversion in adichloromethane (DCM)/n-heptane solvent system, anti-solvent addition,solid vapor diffusion, and slow cooling crystallization techniques in avariety of solvent systems. Isomorphs of Form B characterized in thepresent invention were obtained from the slurry conversion technique indichloromethane (DCM)/n-heptane and an anti-solvent addition techniquein tetrahydrofuran (THF)/n-heptane or chloroform (CHCl₃)/methyltert-butyl ether (MBTE).

Example 4. Preparation of Solid Form C

Form C was prepared from Form A via a slurry conversion crystallizationtechnique in isopropyl alcohol (IPA) and isopropyl acetate (IPAc) at 50°C.

Example 5. Preparation of Solid Form D

Form D was prepared from Form A via an anti-solvent additioncrystallization technique in tetrahydrofuran (THF)/water (H₂O) atroom-temperature (RT) conditions.

Example 6. Preparation of Solid Form E

Form E was prepared from Form A via an anti-solvent additioncrystallization technique in 1,4-dioxane/n-heptane at ambientroom-temperature (RT) conditions.

Example 7. Preparation of Solid Form F

Form F was prepared from Form A via a reverse anti-solvent additioncrystallization technique in 1,4-dioxane/n-heptane at ambientroom-temperature (RT) conditions.

Example 8. Preparation of Solid Form H

Form H was prepared via a solution vapor diffusion crystallizationtechnique in n-heptane at room-temperature (RT) conditions.

Example 9. Preparation of Solid Form I

Form I was prepared via a slow cooling crystallization technique inmethanol (MeOH) at room-temperature (RT) conditions.

Example 10. Preparation of Solid Form J

Form J was prepared via a solid vapor diffusion crystallizationtechnique in MeOH at room-temperature (RT) conditions.

Example 11. Preparation of Solid Form K

Form K was prepared by heating Forms A, B, C, E, or F to elevatedtemperatures. The sample of Form K analyzed was prepared by heating FormF to 100° C.

Example 12. Preparation of Solid Form L

Form L was prepared by storing Form B in a sealed vial at ambientconditions for a month.

Example 13. Preparation of Solid Form M

Form M was prepared by storing Form B in a sealed vial at ambientconditions for a month.

Example 14. Preparation of Solid Form N

Form N was prepared from a reverse anti-solvent addition crystallizationtechnique in 1,4-dioxane/n-heptane when attempting to replicateformation of Form F.

Example 15. Preparation of Solid Form O

Form O was prepared from a water activity crystallization technique inH₂O/acetonitrile (ACN) (0.041:0.959 v/v; a_(w)=0.6). Acetonitrile playsan essential role in Form O formation, and this solvent may be needed toproduce this form.

Example 16. Characterization of Solid Forms A-O by XRPD

A PANalytical Empyrean X-ray powder diffractometer with a 12-wellauto-sampler stage was used for analysis throughout this study. The XRPDparameters used are listed in Table 8. Resolution calibration of theinstrument was performed every 6 months, and sensitivity measurementswere performed after the sample stage was changed. A silicon (Si)pressed powder sample was used as the reference standard.

TABLE 8 Parameters for XRPD Parameters for Reflection Mode X-Raywavelength Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2/Kα1intensity ratio: 0.50 X-Ray tube setting 45 kV, 40 mA Divergence slitAutomatic Scan mode Continuous Scan range (degrees 2θ) 3° to 40° Stepsize (degrees 2θ) 0.017° Scan speed (degrees/min) ~10

Form A: Form A was observed to be crystalline by XRPD, as shown in FIG.1A.

Form B: The XRPD pattern in FIG. 2A shows that Form B-1 is crystalline.The XRPD patterns in FIG. 2B shows that Forms B-1, B-2, and B-3 arecrystalline.

Form C: The XRPD pattern in FIG. 3A shows that Form C is crystalline.

Form D: As shown in the obtained XRPD pattern provided in FIG. 4A, FormD is crystalline. XRPD analysis also indicated that Form D wastransformed to Form A after drying at ambient conditions, as illustratedin FIG. 4B.

Form E: Based on the obtained XRPD pattern of the wet sample in FIG. 5A,Form E was observed to be crystalline. After drying at ambientroom-temperature conditions, Form E transformed to a mixture of Forms Aand C that exhibited low crystallinity.

Form F: The obtained XRPD pattern of the dried sample under vacuum inFIG. 6A shows that Form F is crystalline.

Form H: The obtained XRPD pattern of the wet sample in FIG. 7A showsthat Form H is crystalline. XRPD analysis indicates that Form Htransforms to Form A after drying at ambient conditions for 3 days, asillustrated in FIG. 7B.

Form I: The obtained XRPD pattern of the wet sample in FIG. 8A showsthat Form I is crystalline. XRPD analysis indicates that Form Itransforms to Form A after drying at ambient conditions for 3 days, asillustrated in FIG. 8B.

Form J: The obtained XRPD pattern of the wet sample in FIG. 9A showsthat Form J is crystalline. XRPD analysis indicates that Form Jtransforms to Form A after drying at ambient conditions for 3 days, asillustrated in FIG. 9B.

Form K: The obtained XRPD pattern in FIG. 10A shows that Form K iscrystalline.

Form L: The obtained XRPD pattern in FIG. 11A shows that Form L iscrystalline. After 3 days at ambient conditions, Form L transforms to amixture of Forms B and M, as shown in the XRPD pattern presented in FIG.11B.

Form M: The obtained XRPD pattern in FIG. 12 shows that Form M has lowcrystallinity.

Form N: The XRPD pattern of the dried sample at ambient conditions inFIG. 13A shows that Form N is crystalline. The XRPD pattern in FIG. 13Bshows that overnight, under ambient conditions, Form N transforms toForm A.

Form O: The obtained XRPD pattern in FIG. 14A shows that Form O iscrystalline.

Example 17. Methods of Producing Single Crystals of Form A and Form C

Form A: Single crystals suitable for structure determination wereobtained via slow cooling in isopropyl alcohol from 50° C. to 5° C.

Form C: Single crystals suitable for structure determination wereobtained via slow cooling at a rate of 0.01° C./min in isopropylacetate/acetone (6:1, v/v) co-solvents with Form C seeds, from 25° C. to5° C.

Example 18. Single Crystal X-Ray Diffraction Data of Form A and Form C

X-ray intensity data from prism-like crystals of Form A (Table 9) andForm C (Table 10) were collected at 290(2) K using a Bruker D8 Venturediffractometer (Mo Kα radiation, λ=0.71073 Å). The crystal structures ofForms A and C were solved from the obtained data.

TABLE 9 Crystal data and structural refinement for a single crystal ofForm A: Empirical formula C₂₅H₃₅N₃O₂ Formula weight 409.56 Temperature100(2) K Wavelength 0.71073 Å Crystal system, space group MonoclinicP2₁Unit cell dimensions a = 9.379(3) Å b = 9.922(3) Å c = 12.092(4) Å α =90° β = 101.606(9)° γ = 90° Volume 1102.2(6) Å³ Z, Calculated density 2,1.234 Mg/m³ Absorption coefficient 0.079 mm⁻¹ F(000) 444 Crystal size0.30 × 0.20 × 0.10 mm³ Theta range for data collection 2.22-27.56°Limiting indices −12 ≤ h ≤ 12 −12 ≤ k ≤ 12 −15 ≤ l ≤ 15 Reflectionscollected/unique 23466/5060 [R(int) = 0.0670] Completeness 99.9%Refinement method Full-matrix least-squares on F²Data/restraints/parameters 5060/1/274 Goodness-of-fit on F² 1.071 FinalR indices [I > 2sigma(I)] R₁ = 0.0425 wR₂ = 0.0989 Largest diff. peakand hole 0.309and −0.368 e · Å⁻³ Absolute structure parameter 1.5(11)

TABLE 10 Crystal data and structural refinement for a single crystal ofForm C: Empirical formula C₂₅H₃₅N₃O₂ Formula weight 409.56 Temperature290(2) K Wavelength 0.71073 Å Crystal system, space group OrthorhombicP2₁2₁2₁ Unit cell dimensions a = 9.6642(8) Å b = 9.8676(8) Å c =23.9408(19) Å α = 90° β = 90° γ = 90° Volume 2283.1(3) Å³ Z, Calculateddensity 4, 1.192 mg/m³ Absorption coefficient 0.076 mm⁻¹ F(000) 888Crystal size 0.28 × 0.05 × 0.03 mm³ Theta range for data collection2.71-27.61° Limiting indices −12 ≤ h ≤ 12 −12 ≤ k ≤ 12 −31 ≤ l ≤ 31Reflections collected/unique 33905/5265 [R(int) = 0.0823] Completeness99.3% Refinement method Full-matrix least-squares on F²Data/restraints/parameters 5265/7/272 Goodness-of-fit on F² 1.042 FinalR indices [I > 2sigma(I)] R₁ = 0.0647 wR₂ = 0.1128 Largest diff. peakand hole 0.248 and −0.335 e · Å⁻³ Absolute structure parameter 0.0(19)

Example 19. Unit Cells of the Single-Crystal Structures of Form A andForm C

The unit cell of Form A along the b axis is depicted in FIG. 1B. Theunit cell of Form C along the b axis is depicted in FIG. 3B.

Example 20. Characterization of Solid Forms A-O by Temperature-DependentInstrumental Methods (TGA, DSC, and VT-XRPD)

Thermogravimetric analysis (TGA) data were collected using a TAQ500/Q5000 TGA from TA Instruments, and differential scanningcalorimetry (DSC) was performed using a TA Q200/Q2000 DSC from TAInstruments. The instrument parameters used are provided in Table 11.

TABLE 11 Parameters for TGA and DSC Test Parameters TGA DSC Method RampRamp Sample pan Platinum, open Aluminum, crimped Temperature RT to 350°C. RT to 300° C. Heating rate 10° C./min 10° C./min Purge gas N₂ N₂

To complement the temperature-dependent studies and confirm thesolvation state of the solid forms, solution NMR was collected on aBruker 400 MHz NMR Spectrometer using deuterated dimethyl sulfoxide(DMSO-d₆) as the solvent.

Form A: TGA and DSC were performed and the details provided in FIG. 1C.Thermogravimetric analysis of Form A resulted in a 1.0% weight loss upto 200° C. An endotherm observed on the DSC curve at 157.2° C. (onsettemperature), representing the transformation of Form A to Form K, wasfollowed by a sharp melting peak for Form K at 203.8° C. (onsettemperature). Verification of the transformation to Form K was performedby VT-XRPD, as shown in FIG. 1D.

Form B-1: TGA and DSC were performed, and their respective curves areprovided in FIG. 2C. The TGA curve shows a 2-stage weight loss, with a5.7% loss of residual solvent up to 76° C. followed by an 8.5% loss(desolvation) up to 200° C. The DSC curve exhibits 2 endothermic peaksat 87.2° C. and 211.7° C. (onset temperatures), corresponding to theloss of solvent (transformation to Form K) and the melting point of FormK, respectively. Analysis by XPRD indicates that Form B-1 transforms toForm K upon heating to 100° C., as shown in FIG. 2D. Based on the ¹H NMRdata shown in FIG. 2G, Form B is an n-heptane solvate with a molar ratioof 1:0.4 Compound 1:n-heptane (˜8.9% n-heptane by weight), which is ingood agreement with the TGA result. Residual DCM with a molar ratio of1:0.06 Compound 1:DCM (1.2% by weight) was also observed in the ¹H NMRdata.

Form B-2: The TGA of this isomorph is shown in FIG. 2E along with theTGA curves of the other two isomorphs. The DSC curve of this isomorph,which is depicted in FIG. 2F along with an overlay of the other twoisomorphs, exhibits two endotherms, one at a Toner of 85.4° C. and oneat a Toner of 212.2° C. The ¹H NMR spectrum in FIG. 2H showed that FormB is an n-heptane solvate in a molar ratio of 1:0.3 Compound1:n-heptane, with no THF observed.

Form B-3: The TGA of this isomorph is shown in FIG. 2E along with theTGA curves of the other two isomorphs. The DSC curve of this isomorph,which is depicted in FIG. 2F along with an overlay of the other twoisomorphs, exhibits two endotherms, one at a Toner of 69.2° C. and oneat a Toner of 211.6° C. The ¹H NMR spectrum in FIG. 2I showed that FormB is a chloroform solvate in a molar ratio of 1:0.5 Compound1:chloroform, with residual methyl tert-butyl ether detected.

Form C: TGA and DSC were performed, and their respective curves areprovided in FIG. 3C. The TGA curve shows that a weight loss of 4.3%occurs below 50° C. indicating loosely held solvent or adventitioussolvent, possibly present due to insufficient drying. The DSC curveexhibits 2 endothermic peaks at 183.8° C. and 211.0° C. (onsettemperatures). Further investigation of the endotherm at 183.8° C. wasperformed by heating Form C to 185° C., which resulted in a formtransformation to Form K, as shown in FIG. 3D. Analysis by VT-XRPD wasperformed on Form C, with and without nitrogen (N₂) flow, to investigatepossible rehydration from air. As shown in FIG. 3E, no differences wereobserved with and without N₂, indicating that Form C is an anhydrate.

Form F: TGA and DSC were performed, and their respective curves areprovided in FIG. 6B. The TGA curve shows a total weight loss of 19.7% upto 200° C. The DSC curve exhibits 2 endothermic peaks at 63.1° C. and210.7° C. (onset temperatures), corresponding to the loss of solvent(transformation to Form K) and the melting point of Form K,respectively. This is further evidenced by the transformation of Form Fto Form K after heating to 100° C., as shown in FIG. 6C. Based on the ¹HNMR spectrum shown in FIG. 6D, Form F is a 1,4-dioxane solvate with amolar ratio of 1:0.9 (16.2% 1,4-dioxane by weight), which is in goodagreement with the TGA result. Residual n-heptane at a molar ratio of1:0.03 (0.7% n-heptane by weight) is also observed in the ¹H NMR data.

Form K: TGA and DSC were performed, and their respective curves areprovided in FIG. 11B. The TGA curve shows a weight loss of 1.6% up to200° C., and the DSC curve exhibits an endothermic peak at 211.6° C.(onset temperature), corresponding to the melting endotherm of Form K.Based on the low volatiles content, Form K is an unsolvated material.

Form L: The DSC curve of Form L, shown in FIG. 12C exhibits 2endothermic peaks at 81.7° C. and 210.6° C. (onset temperatures). Thefirst endothermic peak is attributed to the possible loss of solvent orform transformation. The second endothermic peak in the DSC curvematches the melting endotherm of Form K.

Form N: The TGA curve in FIG. 14C shows a 2-step weight loss of 2.5% upto 60° C., followed by 7.1% up to 200° C. The DSC curve exhibits 2endothermic peaks at 75.4° C. and 210.4° C. (onset temperatures),attributed to the loss of solvent (based on ¹H NMR) and the meltingpoint of Form K, respectively. Based on the ¹H NMR result in FIG. 14D,Form N is a 1,4-dioxane solvate with a molar ratio of 1:0.3 Compound1:1,4-dioxane (6.1% 1,4-dioxane by weight), which is in agreement withthe second step weight loss in the TGA analysis.

Form O: A 2-step weight loss of 5.3% up to 55.1° C., followed by 5.9% upto 200° C. is observed in the TGA curve presented in FIG. 15B. The DSCcurve exhibits 3 endothermic peaks at 65.0° C., 168.5° C., and 210.8° C.(onset temperatures), corresponding to the loss of solvent to createForm C, transformation of Form C to Form K, and the melting point ofForm K, respectively. In order to investigate the endotherms observed inthe DSC analysis, Form O was heated to 120° C. resulting in a change toForm C, as shown in FIG. 15C. The ¹H NMR spectrum revealed a molar ratioof 1:0.2 for Form O:ACN (1.9% by weight) after heating to 50° C. inorder to remove residual solvent, as illustrated in FIG. 15D.

Example 21. Hygroscopicity of Forms A, C, and K as Measured by DVS

Dynamic vapor sorption (DVS) was measured via an SMS (SurfaceMeasurement Systems) DVS Intrinsic system. The relative humidity at 25°C. was calibrated against the deliquescence point of LiCl, Mg(NO₃)₂, andKCl. Instrument parameters for the DVS system used throughout this studyare listed in Table 12.

TABLE 13 Parameters for DVS Test Parameters DVS Temperature 25° C.Sample size 10~20 mg Gas and flow rate N₂, 200 mL/min dm/dt 0.002%/minMin. dm/dtstabilityduration 10 min Max. equilibrium time 180 min RHrange 0% RH to 95% RH RH step size (sorption) 10% RH from 0% RHto 90% RH5% RH from 90% RH to 95% RH RH step size (desorption) 10% RH from 90% RHto 0% RH 5% RH from 95% RH to 90% RH

The hygroscopicity of Form A, Form C, and Form K were investigated at25° C. using DVS. The XRPD patterns of each sample before and after DVSwere compared in order to investigate any potential form change.

The DVS isotherm plot of Form A shown in FIG. 1E exhibits 0.06% byweight water uptake at 80% RH and less than 0.12% by weight water uptakeat 95% RH, revealing that Form A is non-hygroscopic. The XRPD pattern inFIG. 1F indicates there is no form change before and after DVS for FormA.

Similarly, the DVS isotherm plot of Form C shown in FIG. 3F exhibits0.12% by weight water uptake at 80% RH and less than 0.30% by weightwater uptake at 95% RH, indicating that Form C is non-hygroscopic. TheXRPD pattern in FIG. 3G shows there is no form change before and afterDVS for Form C.

The DVS isotherm plot of Form K shown in FIG. 11C exhibits 0.18% byweight water uptake at 80% RH and less than 0.35% by weight water uptakeat 95% RH, revealing that Form K is non-hygroscopic. The XRPD pattern inFIG. 11D shows there is no form change before and after DVS for Form K.

Example 22. Interconversion of Form A, C, and K Through SlurryConversion

In one embodiment, the inter-conversion between Forms A, C and K can bestudied in a series of slurry conversion experiments conducted in ethylacetate, n-butanol, and methyl tert-butyl ether (MBTE) at both roomtemperature (RT) and 50° C. Compound 1 can display moderate solubility,and may yield solvated forms during these screening experiments. Resultsof the slurry conversion experiments are summarized in Table 14. Thetransition temperature between Forms A and C was estimated to be ˜17°C., and the transition temperature between Forms K and C was above 100°C.

TABLE 14 Summary of Slurry Conversion Experiments Solvent ConditionInitial Form Final Form Ethyl RT Forms A and K (with Form C seeds) FormC acetate 50° C. Forms A and K Form C n- RT Forms A, C and K Form CButanol 50° C. Forms A, C and K Form C MBTE RT Forms A, C and K Form C50° C. Forms A, C and K Form C

Example 23. Conversion of Form A to Form C with Form C Seed Crystals

Approximately 200 g/L-225 g/L solubilized Compound 1 (originally Form A)in ethyl acetate was heated to a temperature of 65° C. in the presenceof 0.2%-1.0% of seed crystals of Form C for 1-3 hours. The batch canthen be slowly cooled down to a temperature between 25° C.-30° C. for noless than 3 hours to obtain Form C. Seed crystals of Form C can beobtained using the procedure described in Example 4.

XRPD was performed using a Rigaku MiniFlex 600 (Cu Kα radiation at 40 kVtube voltage and 15 mA tube current) with a scanning range of 2° to 40°for 2θ, a step size of 0.01°, and a scanning speed of 1° or 2° perminute. XRPD was used to monitor the conversion from 225 g/L Form A toForm C in ethyl acetate at 65° C. using 1.0% of seed crystals of Form Cwith time, as indicated in FIG. 15.

Example 24. Preparation and Characterization of Form P

During solubility measurements, an XRPD pattern was detected in (a)slurries of Form A in EtOAc at 5° C. (after 1 h) and 20° C. (after 2days), (b) slurries of Form C in EtOAc at 5° C. (after 1 h) and 20° C.(after 7 days). There was no direct match of this solid form's XRPDpattern to other crystal forms of Compound 1. The results indicate thatthis solid form of Compound 1 in EtOAc, termed Form P, is more stablethan both Forms A and C in EtOAc at least at ≤20° C.

The wet cake of Form P (˜5 min air) was dried in two ways: (a) under airat room temperature overnight, and (b) under vacuum at 40° C. for 3hours. Both dried cakes were analyzed by XRPD, 1H-NMR, and TGA. XRPDdata are presented in FIG. 16. NMR data are presented in FIG. 17A FIG.17B. TGA data are presented in FIG. 18A FIG. 18B. The air dried cakegave an XRPD pattern conforming to Form P, about 1% weight loss by TGAup to about 50° C., and EtOAc peaks by ¹H NMR. This indicates that FormP is an EtOAc solvate of Compound 1. The sample of Form P post-ovendrying, on the other hand, gave an XRPD pattern conforming to Form A, noweight loss ≤100° C. by TGA, and no EtOAc peaks by ¹H-NMR. Therefore,the data suggests that Form P is a solvate of Form A and converts toForm A upon drying.

Example 25. Solubility and Relative Stability of Forms A, C and P

Solubility profiles of Forms A, C and P across a range of temperaturecan give an indication of the relative stability of different formswithin different temperature ranges. Sufficient equilibrium solubilitydata were collected experimentally covering 5-70° C. The results arepresented in Table 15 and FIG. 19.

The data indicate that (1) Form C is more stable than Form A across theentire processing temperature range, (2) Form P becomes more stable thanForm C ≤20° C., (3) there is little interconversion between the threeforms around 25˜30° C. due to slow conversion kinetics, (4) Form Pbecomes unstable in EtOAc at ≥35° C. and converts to Form A; and (5)Form P converts into Form A upon drying in air or N₂.

A phase relationship of Forms A, C and P in EtOAc is illustrated in FIG.20. In EtOAc at low temperatures Forms A and C can convert to Form P.Form A can also be generated from Form C at too low of a temperature(e.g., aimed for a better isolation yield).

TABLE 15 Solubility data of Forms A, C, and P. Temper- Solubility(mg/mL) Equili- Crystal Form ature Form P bration Checked by (° C.) FormA Form C (Solvate) Time XRPD 5 NA 5.4 20 h Form P 10 6.6 3 day Form P 158.0 2 day Form P 20 12.4 11.8 11.4 2 day No Form Change 25 — — 12.6 20 hForm P 30 15.5 14.9 — 4 h No Form Change — — 13.5 20 h Form P 40 18.817.9 — 7 h No Form Change — — — 24 h Form P to Form A 50 25   23.7 — 20h No Form Change 60 31.7 29.8 — 4 h No Form Change

OTHER EMBODIMENTS

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A crystalline solid form of Compound 1:

having an XRPD pattern comprising peaks between and including 9.7 to10.1 degrees in 2θ, between and including 11.6 to 12.0 degrees in 2θ,between and including 13.2 to 13.6 degrees in 2θ, between and including14.2 to 14.6 degrees in 2θ, between and including 14.6 to 15.0 degreesin 2θ, between and including 16.8 to 17.2 degrees in 2θ, between andincluding 20.5 to 20.9 degrees in 2θ, between and including 21.3 to 21.7degrees in 2θ, between and including 21.4 to 21.8 degrees in 2θ, andbetween and including 22.4 to 22.8 degrees in 2θ.
 2. The crystallinesolid form of claim 1, wherein the peak between and including 9.7 to10.1 is 9.9 degrees in 2θ, the peak between and including 11.6 to 12.0is 11.8 degrees in 2θ, the peak between and including 13.2 to 13.6 is13.4 degrees in 2θ, the peak between and including 14.2 to 14.6 is 14.4degrees in 2θ, the peak between and including 14.6 to 15.0 degrees is14.8 in 20, the peak between and including 16.8 to 17.2 is 17.0 degreesin 2θ, the peak between and including 20.5 to 20.9 is 20.7 degrees in2θ, the peak between and including 21.3 to 21.7 is 21.5 degrees in 2θ,the peak between and including 21.4 to 21.8 is 21.6 degrees in 2θ, andthe peak between and including 22.4 to 22.8 is 22.6 degrees in 2θ.
 3. Acrystalline solid form of Compound 1:

having an XRPD pattern comprising peaks between and including 9.7 to10.1 degrees in 2θ, between and including 14.6 to 15.0 degrees in 2θ,between and including 16.8 to 17.2 degrees in 2θ, between and including20.5 to 20.9 degrees in 2θ, between and including 21.3 to 21.7 degreesin 2θ.
 4. The crystalline solid form of claim 3, wherein the peakbetween and including 9.7 to 10.1 is 9.9 degrees in 2θ, the peak betweenand including 14.6 to 15.0 is 14.8 degrees in 2θ, the peak between andincluding 16.8 to 17.2 is 17.0 degrees in 2θ, the peak between andincluding 20.5 to 20.9 is 20.7 degrees in 2θ, and the peak between andincluding 21.3 to 21.7 is 21.5 degrees in 2θ.
 5. The A crystalline solidform of Compound 1:

having an XRPD pattern comprising peaks at 9.9 degrees in 2θ, 14.8degrees in 2θ, 17.0 degrees in 2θ, 20.7 degrees in 2θ, and 21.5 degreesin 2θ.